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WO2023115165A1 - Composés - Google Patents

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Publication number
WO2023115165A1
WO2023115165A1 PCT/AU2022/051591 AU2022051591W WO2023115165A1 WO 2023115165 A1 WO2023115165 A1 WO 2023115165A1 AU 2022051591 W AU2022051591 W AU 2022051591W WO 2023115165 A1 WO2023115165 A1 WO 2023115165A1
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WO
WIPO (PCT)
Prior art keywords
heterocycloalkyl
cycloalkyl
alkyl
haloalkyl
alkynyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/AU2022/051591
Other languages
English (en)
Inventor
Samuel BANISTER
William Jorgensen
Jinlong Tan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Psylo Pty Ltd
Original Assignee
Psylo Pty Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AU2021904268A external-priority patent/AU2021904268A0/en
Priority to IL313857A priority Critical patent/IL313857A/en
Priority to EP22908927.1A priority patent/EP4452979A4/fr
Priority to CN202280091203.9A priority patent/CN118974044A/zh
Priority to KR1020247024904A priority patent/KR20240128059A/ko
Priority to JP2024538669A priority patent/JP2025501141A/ja
Application filed by Psylo Pty Ltd filed Critical Psylo Pty Ltd
Priority to US18/722,007 priority patent/US20250163044A1/en
Priority to AU2022422215A priority patent/AU2022422215A1/en
Priority to MX2024007911A priority patent/MX2024007911A/es
Priority to CA3241845A priority patent/CA3241845A1/fr
Publication of WO2023115165A1 publication Critical patent/WO2023115165A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems

Definitions

  • serotonergic drugs such as antidepressants, serotonin reuptake inhibitors, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, and others are commercially available to treat mental illnesses.
  • these therapeutics provide limited benefit when compared to a placebo. Additionally, these therapeutics can result in a wide range of side effects including loss of libido, insomnia, fatigue, weight gain, and others.
  • these drugs continue to be used to treat neuropsychiatric conditions as well as a broad range of auxiliary medical indications. There have been limited advances in new treatment options since many of these drugs were released, and the pharmaceutical industry has come under increased financial pressure to de-emphasise neuroscience programmes entirely.
  • Psilocybin is rapidly metabolized to the bioactive compound psilocin, which produces a state of altered consciousness including changes in perception, visual hallucinations, and distorted sense of space, time, and self. Many patients report spiritual or “mystical” experiences which have profound and lasting impact on the patients’ mood and behaviour. Psilocybin has shown promise in more than 50 clinical trials for neuropsychiatric indications, including numerous anxiety disorders, obsessive-compulsive disorder, anorexia nervosa, alcohol dependence, and tobacco addiction.
  • Psilocybin and other psychedelic compounds such as N,N- dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) have both immediate and persistent effects on mental state, with the latter extending far beyond the duration of action, possibly as a result of their ability to incite increased neuroplasticity, promote neural outgrowth, and increase spine density of the synaptic neurons in the brain.
  • DMT N,N- dimethyltryptamine
  • 5-MeO-DMT 5-methoxy-N,N-dimethyltryptamine
  • 5-HT2A the primary target
  • 5-HT2B receptors a cardiac liability antitarget
  • 5-HT1A an anxiolytic target
  • 5-HT2C receptors a disease-relevant target for obesity and some genetic epilepsies, for example
  • the present disclosure provides a compound of formula (I): or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof, wherein R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C14 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C
  • R 1 and R 2 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl and C4-14 alkylenecycloalkyl.
  • R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following:
  • R 1 and R 2 are combined with the atoms to which they are attached to form C3-6 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C1- 8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR 4 , wherein R 4 is defined as in any one of the foregoing paragraph
  • R 3 is hydrogen.
  • R 3 and one of R 1 and R 2 are combined with the atoms to which they are attached to form a C3-8 heterocycloalkyl, said C3-8 heterocycloalkyl being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1- 8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO
  • R 7 , R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1- alkyleneP(O)(OR 13 ) S(O)
  • R 7 , R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycl
  • R 7 , R 8 , R 9 , R 10 and R 11 when present are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and OR 13 wherein R 13 is selected from C1-6 alkyl and C1-6 haloalkyl, and the other of R 7 , R 8 R 9 , R 10 and R 11 are each hydrogen.
  • R 7 (if present) is selected from H and C1-6alkyl, preferably R 7 (if present) is H.
  • R 8 and R 9 when present are combined with the atoms to which they are each attached to form a C5-8 heterocycloalkyl or C5-10 heteroaryl, said C5-8 heterocycloalkyl and C5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached; said C5-8 heterocycloalkyl and C5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, CO 2 H, CO 2 CH 3 , C(O)NH 2 , C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6 haloalkyl.
  • R 8 and R 9 are combined to form a C 5-8 heterocycloalkyl or C 5-10 heteroaryl selected from the following: wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached.
  • L is C1-4 alkylene. In some embodiments, L is methylene.
  • R 6 is selected from hydrogen and C1-6 alkyl. In any one of the herein disclosed embodiments, R 6 is hydrogen.
  • X 1 is NH or N.
  • the compound of formula (I) has the formula (II): wherein R 1 , R 2 , R 3 , R 7 , Z 1 , Z 2 , Z 3 and Z 4 are defined as in any one of the foregoing paragraphs; and wherein one or more of Z 1 , Z 2 , Z 3 and Z 4 is N.
  • the compound of formula (I) has the formula (IIa): wherein R 1 , R 2 , R 3 , R 7 , R 9 , R 10 and R 11 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (II) has the formula (IIb): wherein R 1 , R 2 , R 3 , R 7 , R 8 , R 10 and R 11 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) has the formula (IIc): wherein R 1 , R 2 , R 3 , R 7 , R 8 , R 9 and R 11 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) has the formula (IId): wherein R 1 , R 2 , R 3 , R 7 , R 8 , R 9 and R 10 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) has the formula (III): wherein R 1 , R 2 , R 3 , Z 1 , Z 2 , Z 3 and Z 4 are defined as in any one of the foregoing paragraphs. In some embodiments, the compound of formula (I) has the formula (IIIa): wherein R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are defined as in any one of the foregoing paragraphs. In some embodiments, the compound of formula (I) has the formula (IV): wherein X2 is O or S, and R 1 , R 2 , R 3 , Z 1 , Z 2 , Z 3 and Z 4 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) has the formula (IVa): wherein R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are defined as in any one of the foregoing paragraphs.
  • X 1 is O.
  • the compound of formula (I) has the formula (V): wherein R 1 , R 2 , R 3 , Z 1 , Z 2 , Z 3 and Z 4 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) has the formula (Va): wherein R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are defined as in any one of the foregoing paragraphs. In some embodiments, the compound of formula (I) is selected from any one of the following:
  • the present disclosure provides a medicament comprising a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof.
  • a pharmaceutical composition comprising a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof, an additional therapeutic agent, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method of treating a disease, disorder or condition by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I): or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof, wherein R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C14 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C1-6 alkyl, C
  • R 1 and R 2 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl and C 4-14 alkylenecycloalkyl. In some embodiments of the method, R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following:
  • R 1 and R 2 are combined with the atoms to which they are attached to form C3-6 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from
  • R 3 is hydrogen. In some embodiments of the method, R 3 and one of R 1 and R 2 are combined with the atoms to which they are attached to form a C3-8 heterocycloalkyl, said C3-12 heterocycloalkyl being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, SR 4 , NO2, SO2R 4 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO
  • R 7 , R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2- 6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )
  • R 7 , R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2- 6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkylenehe
  • R 7 , R 8 R 9 , R 10 and R 11 when present are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and OR 13 wherein R 13 is selected from C1-6 alkyl and C1-6 haloalkyl, and the other of R 7 , R 8 R 9 , R 10 and R 11 are each hydrogen.
  • R 8 and R 9 when present are combined with the atoms to which they are each attached to form a C5-8 heterocycloalkyl or C5-10 heteroaryl, said C5-8 heterocycloalkyl and C5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached; said C5-8 heterocycloalkyl and C5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6 haloalkyl.
  • halogen O
  • CN CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6 haloal
  • R 8 and R 9 are combined to form a C 5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached.
  • L is C1-4 alkylene. In some embodiments of the method, L is methylene.
  • R 6 is selected from hydrogen and C1-6 alkyl. In some embodiments of the method, R 6 is hydrogen.
  • X 1 is NH or N.
  • the compound of formula (I) has the formula (II): wherein R 1 , R 2 , R 3 , , R 7 , , Z 1 , Z 2 , Z 3 and Z 4 are defined as in any one of the foregoing paragraphs; and wherein one or more of Z 1 , Z 2 , Z 3 and Z 4 is N.
  • the compound of formula (I) has the formula (IIa): wherein R 1 , R 2 , R 3 , R 7 , R 9 , R 10 and R 11 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) has the formula (IIb): wherein R 1 , R 2 , R 3 , R 7 , R 8 , R 10 and R 11 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) has the formula (IIc): wherein R 1 , R 2 , R 3 , R 7 , R 8 , R 9 and R 11 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) has the formula (IId): wherein R 1 , R 2 , R 3 , R 7 , R 8 , R 9 and R 10 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) has the formula (III): wherein R 1 , R 2 , R 3 , , Z 1 , Z 2 , Z 3 and Z 4 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) has the formula (IIIa): wherein R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) has the formula (IV): wherein X2 is O or S, and R 1 , R 2 , R 3 , , Z 1 , Z 2 , Z 3 and Z 4 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) has the formula (IVa): wherein R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) has X 1 as O.
  • the compound of formula (I) has the formula (V): wherein R 1 , R 2 , R 3 , , Z 1 , Z 2 , Z 3 and Z 4 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) has the formula (Va): ( a) wherein R 1 , R 2 , R 3 , R 8 , R 9 , R 10 and R 11 are defined as in any one of the foregoing paragraphs.
  • the compound of formula (I) is selected from any one of the following: , or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof.
  • the present disclosure provides a method of treating a disease, disorder or condition by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) as defined in any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof, in combination with another known agent useful for treatment of a disease, disorder or condition by activation of a serotonin receptor.
  • the present disclosure provides a method of treating a mental illness, the method comprising administering to a subject in need thereof a compound of formula (I) as defined in any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof.
  • the mental illness is selected from anxiety disorders; depression; mood disorders; psychotic disorders; impulse control and addiction disorders; drug addiction; obsessive-compulsive disorder (OCD); post-traumatic stress disorder (PTSD); stress response syndromes; dissociative disorders; depersonalization disorder; factitious disorders; sexual and gender disorders; somatic symptom disorders; hallucinations; delusions; psychosis; and combinations thereof
  • CNS central nervous system
  • the method comprising administering to a subject in need thereof a compound of formula (I) as defined in any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof.
  • the CNS disease, disorder or condition and/or neurological disease, disorder or condition is selected from neurological diseases including neurodevelopmental diseases and neurodegenerative diseases such as Alzheimer’s disease; presenile dementia; senile dementia; vascular dementia; Lewy body dementia; cognitive impairment, Parkinson’s disease and Parkinsonian related disorders such as Parkinson dementia, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infections; CNS inflammation; stroke; multiple sclerosis; Huntington’s disease; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; hereditary ataxias; neuro-otological and eye movement disorders; neurodegenerative diseases of the retina amyotrophic lateral sclerosis; tardive dyskinesias; hyperkinetic disorders; attention deficit hyperactivity disorder and attention deficit disorders; restless leg syndrome; Tourette's syndrome; schizophrenia; autism spectrum disorders; tuberous sclerosis; Rett syndrome; cerebral palsy; disorders of the reward system including eating disorders such as anorexia nervos
  • the present disclosure provides a method for increasing neuronal plasticity and/or increasing dendritic spine density, the method comprising contacting a neuronal cell with a compound of formula (I) as defined in any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N- oxide, stereoisomer, metabolite, polymorph or prodrug thereof, in an amount sufficient to increase neuronal plasticity and/or increase dendritic spine density of the neuronal cell.
  • the present disclosure provides methods of treating weight, comprising administering an effective amount of a compound of the invention to a subject in need thereof.
  • Treatment of weight may include treating weight gain; weight loss; metabolic disorder; weight gain associated with pharmaceutical intervention; weight gain associated with a mental illness (including those described herein); eating disorders such as anorexia, bulimia, cachexia, etc.; eating behaviour; obesity; diabetes; insulin resistance; pre-diabetes; glucose intolerance; hyperlipidemia; and cardiovascular disease.
  • eating disorders such as anorexia, bulimia, cachexia, etc.; eating behaviour; obesity; diabetes; insulin resistance; pre-diabetes; glucose intolerance; hyperlipidemia; and cardiovascular disease.
  • the present disclosure provides a method for activating a serotonin receptor in a cell either in a biological sample or in a patient comprising administering a compound of formula (I) as defined in any one of the herein disclosed embodiments to the cell. Any embodiment herein shall be taken to apply mutatis mutandis to any other embodiment unless specifically stated otherwise.
  • Figure 6 Time immobilisation results from tail suspension test (TST) experiments described in Example 51 for compounds P-3.2HCl (3mg/kg; 10mg/kg) and P-8.2HCl (3mg/kg; 10mg/kg; 30mg/kg) compared with ketamine (10mg/kg) and vehicle.
  • TST tail suspension test
  • treatment or “treating” of a subject includes delaying, slowing, stabilizing, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the disease or condition, the sign or symptom of the disease or condition, or the risk of (or susceptibility to) the disease or condition.
  • treating refers to any indication of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; lessening severity of the disease; stabilization, diminishing of signs or symptoms or making the injury, pathology or condition more tolerable to the individual; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating.
  • the methods of the present invention can be to prevent or reduce the severity, or inhibit or minimise progression, of a sign or symptom of a disease or condition as described herein. As such, the methods of the present invention have utility as treatments as well as prophylaxes.
  • preventing or “prevention” is intended to refer to at least the reduction of likelihood of the risk of (or susceptibility to) acquiring a disease or disorder (ie causing at least one of the clinical signs or symptoms of the disease not to develop in an individual that may be exposed to or predisposed to the disease but does not yet experience or display signs or symptoms of the disease).
  • Biological and physiological parameters for identifying such patients are provided herein and are also well known by physicians.
  • the term “subject” or “patient” can be used interchangeably with each other.
  • the term “individual” or “patient” refers to an animal that is treatable by the compound and/or method, respectively, including but not limited to, for example, dogs, cats, horses, sheep, pigs, cows, and the like, as well as human, non-human primates. Unless otherwise specified, the “subject” or “patient” may include both male and female genders. Further, it also includes a subject or patient, preferably a human, suitable for receiving treatment with a pharmaceutical composition and/or method of the present invention.
  • selective means a greater activity against a first target (e.g., a 5-HT receptor subtype) relative to a second target (e.g., a second 5-HT receptor subtype).
  • a compound has a selectivity of at least 1.25-fold, at least 1.5 fold, at least 2- fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 10-fold or at least 100-fold greater towards a first target relative to a second target.
  • a compound described herein is selective towards the 5-HT2A receptor relative to one or more other 5-HT receptor subtypes such as 5-HT2B and/or 5-HT2C, preferably 5-HT2B.
  • a compound described herein is selective towards the 5-HT2c receptor relative to one or more other 5-HT receptor subtypes such as 5-HT2A and/or 5-HT2B, preferably 5-HT2B.
  • alkyl refers to a straight or branched chain hydrocarbon radical having from one to twelve carbon atoms, or any range between, i.e. it contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.
  • the alkyl group is optionally substituted with substituents.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like.
  • C1-C2 alkyl refers to an alkyl group, as defined herein, containing at least 1, and at most 2, 3 or 6 carbon atoms respectively, or any range in between (eg alkyl groups containing 2-5 carbon atoms are also within the range of C1-C6).
  • alkylene refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated, and linking at least two other groups, i.e., a divalent hydrocarbon radical.
  • the two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group.
  • a straight chain alkylene can be the bivalent radical of –(CH2)n–, where n is 1, 2, 3, 4, 5 or 6.
  • Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.
  • alkenyl whether it is used alone or as part of another group, means a straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends.
  • the number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cn1-n2”.
  • C2-6 alkylene means an alkylene group having 2, 3, 4, 5 or 6 carbon atoms.
  • alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3- hexadienyl, 1 ,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl.
  • alkynyl as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkynyl groups containing at least one triple bond.
  • the number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cn1-n2”.
  • C2-6 alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.
  • alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2- pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl.
  • cycloalkyl is intended to include mono-, bi- or tricyclic alkyl groups.
  • the number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the prefix “Cn1-n2”.
  • C3-8 cycloalkyl means an cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms.
  • cycloalkyl groups have from 3 to 12, from 3 to 10, from 3 to 8, from 3 to 6, from 3 to 5 carbon atoms in the ring(s).
  • cycloalkyl groups have 5 or 6 ring carbon atoms.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the cycloalkyl group has from 3 to 8, from 3 to 7, from 3 to 6, from 4 to 6, from 3 to 5, or from 4 to 5 ring carbon atoms.
  • Bi- and tricyclic ring systems include bridged, spiro, and fused cycloalkyl ring systems.
  • bi- and tricyclic ring cycloalkyl systems include, but are not limited to, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, adamantyl, and decalinyl.
  • alkylenecycloalkyl refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component links the cycloalkyl component to the point of attachment ⁇
  • the alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the cycloalkyl component and to the point of atachment. In some instances, the alkyl component can be absent.
  • the alkyl component can include any number of carbons, such as C1-6, C1-2, C1-3, C1-4, C1-5, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6.
  • the cycloalkyl component is as defined herein.
  • the numerical range from x to y in “Cx-y alkylenecycloalkyl” relates to the total number of alkyl carbons and cycloalkyl ring atoms.
  • Exemplary alkylenecycloalkyl groups include, but are not limited to, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl and methylenecyclohexyl.
  • aryl refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings.
  • the number of carbon atoms that are possible in the referenced aryl group are indicated by the prefix “C n1-n2 ”.
  • C6-12 aryl means an aryl group having 6, 7, 8, 9, 10, 11 or 12 carbon atoms.
  • Aryl groups can include any suitable number of ring atoms, such as, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, as well as from 6 to 10, 6 to 12, or 6 to 14 ring members.
  • Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group.
  • aryl groups include phenyl, naphthyl and biphenyl.
  • Other aryl groups include benzyl, having a methylene linking group. Some aryl groups have from 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl.
  • alkylenearyl refers to a radical having an alkyl component and an aryl component, where the alkyl component links the aryl component to the point of attachment.
  • the alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the aryl component and to the point of attachment.
  • the alkyl component can include any number of carbons, such as C1-6, C1- 2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. In some instances, the alkyl component can be absent.
  • the aryl component is as defined above. The numerical range from x to y in “Cx-y alkylenearyl” relates to the total number of alkyl carbons and aryl ring atoms.
  • alkylenearyl groups include, but are not limited to, benzyl and ethylenephenyl.
  • alkoxy refers to an alkyl group as defined herein covalently bound via an O linkage. The alkoxy group is optionally substituted with substituents. Examples of “alkoxy” as used herein include, but are not limited to methoxy, ethoxy, propoxy, isoproxy, butoxy, iso-butoxy, tert-butoxy and pentoxy.
  • C1-C2 alkoxy refers to an alkoxy group, as defined herein, containing at least 1, and at most 2, 3 or 6 carbon atoms respectively, or any range in between (eg alkoxy groups containing 2-5 carbon atoms are also within the range of C1-C6).
  • alkylamine refers to an alkyl group as defined herein having one or more amino groups. The amino groups can be primary, secondary or tertiary. The alkyl amine can be further substituted with a hydroxy group to form an amino- hydroxy group.
  • alkylamines include, but are not limited to, ethyl amine, propyl amine, isopropyl amine, ethylene diamine and ethanolamine.
  • the amino group can link the alkyl amine to the point of attachment with the rest of the compound, be at the omega position of the alkyl group, or link together at least two carbon atoms of the alkyl group.
  • C1-C2 alkylamine refers to an alkylamine group, as defined herein, containing at least 1, and at most 2, 3 or 6 carbon atoms respectively, or any range in between (e.g., alkylamine groups containing 2-5 carbon atoms are also within the range of C1-C6).
  • alkylsulfonyl refers to an alkyl group as defined herein having one or more sulfonyl groups.
  • the sulfonyl group can link the alkylsulfonyl to the point of attachment with the rest of the compound, be at the omega position of the alkyl group, or link together at least two carbon atoms of the alkyl group.
  • the terms "C1-C2 alkylsulfonyl”, “C1-C3 alkylsulfonyl” and “C1-C6 alkylsulfonyl” refer to an alkylsulfonyl group, as defined herein, containing at least 1, and at most 2, 3 or 6 carbon atoms respectively, or any range in between (e.g., alkylsulfonyl groups containing 2-5 carbon atoms are also within the range of C1-C6).
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen.
  • heteroatoms include nitrogen, oxygen, sulfur and phosphorus.
  • Preferred heteroatoms include N, O and S, preferably N and O.
  • heteroromoiety as used herein means a chemical group comprising a heteroatom.
  • heteromoieties include O, S, S(O), SO2, N and NH.
  • substituted as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest.
  • a "ring substituent” may be a moiety such as a halogen, alkyl group, or other substituent described herein that is covalently bonded to an atom, preferably a carbon or nitrogen atom, that is a ring member.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated substituents, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound, ie, a compound that can be isolated, characterized and tested for biological activity.
  • substituents include but are not limited to C1-C6 alkyl, C1-C6 haloalkyl, C1- C6 haloalkoxy, C1-C6 hydroxyalkyl, C3-C7 heterocyclyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfonylamino, arylsulfonoamino, alkylcarboxy, alkylcarboxyamide, oxo, hydroxy, mercapto, amino, acyl, carboxy, carbamoyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aroyl, aroylamino, heteroaroyl, acyloxy, aroyloxy, heteroaroyl
  • the substituents include amino, halo, C1-C6 alkyl, amido, hydroxyl.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) and the term “halo” refers to the halogen radicals fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-I).
  • halo is fluoro or chloro.
  • haloalkyl refers to an alkyl group as defined herein in which one or more (up to all) of the available hydrogen atoms have been replacd with a halogen.
  • perfluoro can be used to define a compound or radical where all the hydrogens are replaced with fluorine.
  • perfluoromethyl refers to 1,1,1 -trifluoromethyl.
  • C1-C2 haloalkyl refers to a haloalkyl group, as defined herein, containing at least 1, and at most 2, 3 or 6 carbon atoms respectively, or any range in between (e.g. haloalkyl groups containing 2- 5 carbon atoms are also within the range of C1-C6).
  • a C1 haloalkyl group could be, but is not limited to, fluoromethyl, or difluoromethyl, or trifluoromethyl.
  • haloalkenyl refers to an alkenyl group as defined above in which one or more of the available hydrogen atoms have been replaced with a halogen.
  • C 1 - 6 haloalkenyl (or “C 1 -C 6 haloalkenyl”) refers to a C 1 to C 6 linear or branched alkenyl group as defined above with one or more halogen substituents.
  • haloalkynyl refers to an alkynyl group as defined above in which one or more of the available hydrogen atoms have been replaced with a halogen.
  • C1-6 haloalkynyl (or “C1-C6 haloalkynyl”) refers to a C1 to C6 linear or branched alkynyl group as defined above with one or more halogen substituents.
  • haloalkoxy refers to an alkoxy group as defined herein substituted with at least one halogen.
  • amino or “amine” refers to the group -NH2.
  • substituted amino or “secondary amino” refers to an amino group having a hydrogen replaced with, for example a C1-C6 alkyl group (“C1-C6 alkylamino”), an aryl or aralkyl group (“arylamino”, “aralkylamino”) and so on.
  • C1-C3 alkylamino groups are preferred, such as for example, methylamino (NHMe), ethylamino (NHEt) and propylamino (NHPr).
  • disubstituted amino or “tertiary amino” refers to an amino group having the two hydrogens replaced with, for example a C1-C6alkyl group, which may be the same or different (“dialkylamino”), an aryl and alkyl group (“aryl(alkyl)amino”) and so on.
  • Di(C1-C3alkyl)amino groups are preferred, such as for example, dimethylamino (NMe2), diethylamino (NEt2), dipropylamino (NPr2) and variations thereof (eg N(Me)(Et) and so on).
  • nitro refers to the group –NO2.
  • cyano and “nitrile” refer to the group –CN.
  • amido or “amide” refers to the group -C(O)NH2.
  • substituted amido or “substituted amide” refers to an amido group having a hydrogen replaced with, for example a C1-C6 alkyl group (“C1-C6 alkylamido” or “C1-C6 alkylamide”), an aryl (“arylamido”), aralkyl group (“aralkylamido”) and so on.
  • C1-C3 alkylamide groups are preferred, such as for example, methylamide (-C(O)NHMe), ethylamide (-C(O)NHEt) and propylamide (-C(O)NHPr) and includes reverse amides thereof (eg NHMeC(O)-, -NHEtC(O)- and –NHPrC(O)-).
  • disubstituted amido or “disubstituted amide” refers to an amido group having the two hydrogens replaced with, for example a C1-C6alkyl group (“di(C1-C6 alkyl)amido” or “di(C1-C6 alkyl)amide”), an aralkyl and alkyl group (“alkyl(aralkyl)amido”) and so on.
  • Di(C1-C3 alkyl)amide groups are preferred, such as for example, dimethylamide (- C(O)NMe2), diethylamide (-C(O)NEt2) and dipropylamide ((-C(O)NPr2) and variations thereof (eg C(O)N(Me)Et and so on) and includes reverse amides thereof.
  • sulfonyl refers to the group -SO2H.
  • substituted sulfonyl refers to a sulfonyl group having the hydrogen replaced with, for example a C1-C6 alkyl group (“sulfonylC1-C6 alkyl”), an aryl (“arylsulfonyl”), an aralkyl (“aralkylsulfonyl”) and so on.
  • Sulfonyl C1-C3 alkyl groups are preferred, such as for example, -SO2Me, -SO2Et and -SO2Pr.
  • sulfonylamido or “sulfonamide” refers to the group -SO2NH2.
  • substituted sulfonamido or “substituted sulphonamide” refers to an sulfonylamido group having a hydrogen replaced with, for example a C1-C6 alkyl group (“sulfonylamidoC1-C6 alkyl”), an aryl (“arylsulfonamide”), aralkyl (“aralkylsulfonamide”) and so on.
  • SulfonylamidoC1-C3 alkyl groups are preferred, such as for example, SO2NHMe, SO2NHEt and -SO2NHPr and includes reverse sulfonamides thereof (e.g.
  • disubstituted sufonamido or “disubstituted sulphonamide” refers to an sulfonylamido group having the two hydrogens replaced with, for example a C1-C6 alkyl group, which may be the same or different (“sulfonylamidodi(C1-C6 alkyl)”), an aralkyl and alkyl group (“sulfonamido(aralkyl)alkyl”) and so on.
  • Sulfonylamidodi(C1-C3 alkyl) groups are preferred, such as for example, -SO2NMe2, -SO2NEt2 and -SO2NPr2 and variations thereof (eg SO2N(Me)Et and so on) and includes reserve sulfonamides thereof (eg –N(Me)SO2Me and so on).
  • the term “sulfate” refers to the group OS(O)2OH and includes groups having the hydrogen replaced with, for example a C1-C6 alkyl group (“alkylsulfates”), an aryl (“arylsulfate”), an aralkyl (“aralkylsulfate”) and so on.
  • C1-C3 alkylsulfates are preferred, such as for example, OS(O)2OMe, OS(O)2OEt and OS(O)2OPr.
  • the term “sulfonate” refers to the group SO 3 H and includes groups having the hydrogen replaced with, for example a C1-C6 alkyl group (“alkylsulfonate”), an aryl (“arylsulfonate”), an aralkyl (“aralkylsulfonate”) and so on.
  • C1-C3 alkylsulfonates are preferred, such as for example, SO3Me, SO3Et and SO3Pr.
  • amino acid refers to a moiety containing an amino group and a carboxyl group linked by at least one carbon.
  • An amino acid may refer a natural or non-natural amino acid, preferably a natural amino acid such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, preferably the amino acid is arginine, lysine or histidine, most preferably lysine.
  • carboxylate or “carboxyl” refers to the group -COO- or -COOH.
  • carbamate or “carbomyl” refers to the group –OC(O)NH2.
  • the carbamate may be substituted, or may be disubstituted, for example with an alkyl group such as but not limited to C1-C6 alkyl.
  • carbonate refers to the group –OC(O)O- or –OC(O)OH.
  • alkylcarbonate refers to a carbonate group having the hydrogen replaced with, for example a C1-C6 alkyl group, an aryl or aralkyl group (“arylcarbonate” or “aralkylcarbonate”) and so on.
  • CO3C1-C3alkyl groups are preferred, such as for example, methylcarbonate (CO3Me), ethylcarbonate (CO3Et) and propylcarbonate (CO3Pr).
  • esters refers to a carboxyl group having the hydrogen replaced with, for example a C1-C6 alkyl group (“carboxylC1-C6 alkyl” or “alkylester”), an aryl or aralkyl group (“arylester” or “aralkylester”) and so on.
  • CO2C1-C3 alkyl groups are preferred, such as for example, methylester (CO2Me), ethylester (CO2Et) and propylester (CO2Pr) and includes reverse esters thereof (eg –OC(O)Me, -OC(O)Et and –OC(O)Pr).
  • heterocyclyl refers to a moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound which moiety has from 3 to 12 ring atoms (unless otherwise specified), of which 1, 2, 3, 4 or more are ring heteroatoms, for example independently selected from O, S and N, or ring heteromoieties, for example independently selected from O, S, S(O), SO 2 , N and NH.
  • a heterocyclyl group contains the prefix Cn1-n2 or “n1 to n2” this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1, 2, 3, 4 or more, of the ring atoms is replaced with a heteroatom or heteromoiety.
  • the prefixs 3-, 4-, 5-, 6-, 7-, 8-, 9- and 10- membered denote the number of ring atoms, or range of ring atoms, whether carbon atoms or heteroatoms.
  • C3-10 heterocyclyl or “3-10 membered heterocylyl”, as used herein, pertains to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms.
  • heterocylyl groups include 5-6-membered monocyclic heterocyclyls and 9-10 membered fused bicyclic heterocyclyls.
  • Examples of monocyclic heterocyclyl groups include, but are not limited to, those containing one nitrogen atom such as aziridine (3-membered ring), azetidine (4- membered ring), pyrrolidine (tetrahydropyrrole), pyrroline (eg 3-pyrroline, 2,5- dihydropyrrole), 2Hpyrrole or 3H-pyrrole (isopyrrole, isoazole) or pyrrolidinone (5- membered rings), piperidine, dihydropyridine, tetrahydropyridine (6-membered rings), and azepine (7membered ring); those containing two nitrogen atoms such as imidazoline, pyrazolidine (diazolidine), imidazoline, pyrazoline (dihydropyrazole) (5- membered rings), piperazine (6membered ring); those containing one oxygen atom such as oxirane (3-membered ring), oxetane (4
  • Heterocyclyls also encompass heteroaryl (aromatic heterocyclyls) and heterocycloalkyl (non-aromatic heterocyclyls). Such groups may be substituted or unsubstituted.
  • aromatic heterocyclyl may be used interchangeably with the term “heteroaromatic” or the term “heteroaryl” or “hetaryl”.
  • the heteroatoms in the aromatic heterocyclyl group may be independently selected from N, S and O.
  • the aromatic heterocyclyl groups may comprise 1, 2, 3, 4 or more ring heteroatoms.
  • heteroaryl group contains the prefix Cn1-n2 or “n1 to n2” this prefix indicates the number of carbon atoms in the corresponding aryl group, in which one or more, suitably 1, 2, 3, 4 or more, of the ring atoms is replaced with a heteroatom.
  • fused aromatic heterocyclyl groups only one of the rings may contain a heteroatom and not all rings must be aromatic.
  • “Heteroaryl” is used herein to denote a heterocyclic group having aromatic character and embraces aromatic monocyclic ring systems and polycyclic (eg bicyclic) ring systems containing one or more aromatic rings.
  • aromatic heterocyclyl also encompasses pseudoaromatic heterocyclyls.
  • aromatic heterocyclyl refers to a ring system which is not strictly aromatic, but which is stabilized by means of delocalization of electrons and behaves in a similar manner to aromatic rings.
  • aromatic heterocyclyl therefore covers polycyclic ring systems in which all of the fused rings are aromatic as well as ring systems where one or more rings are non-aromatic, provided that at least one ring is aromatic. In polycyclic systems containing both aromatic and non-aromatic rings fused together, the group may be attached to another moiety by the aromatic ring or by a non-aromatic ring.
  • heteroaryl groups are monocyclic and bicyclic groups containing from five to ten ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or two fused five membered rings.
  • Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Aromatic heterocyclyl groups may be 5-membered or 6-membered mono-cyclic aromatic ring systems.
  • 5-membered monocyclic heteroaryl groups include but are not limited to furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including 1,2,3 and 1,2,4 oxadiazolyls and furazanyl i.e.1,2,5-oxadiazolyl), thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (including 1,2,3, 1,2,4 and 1,3,4 triazolyls), oxatriazolyl, tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls) and the like.
  • 6-membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, oxazinyl, dioxinyl, thiazinyl, thiadiazinyl and the like.
  • 6-membered aromatic heterocyclyls containing nitrogen include pyridyl (1 nitrogen), pyrazinyl, pyrimidinyl and pyridazinyl (2 nitrogens).
  • Aromatic heterocyclyl groups may also be bicyclic or polycyclic heteroaromatic ring systems such as fused ring systems (including purine, pteridinyl, napthyridinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl and the like) or linked ring systems (such as oligothiophene, polypyrrole and the like).
  • fused ring systems including purine, pteridinyl, napthyridinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl and the like
  • linked ring systems such as oligothiophene, polypyrrole and the like.
  • Fused ring systems may also include aromatic 5-membered or 6-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like, such as 5- membered aromatic heterocyclyls containing nitrogen fused to phenyl rings, 5- membered aromatic heterocyclyls containing 1 or 2 nitrogens fused to phenyl ring.
  • aromatic 5-membered or 6-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like, such as 5- membered aromatic heterocyclyls containing nitrogen fused to phenyl rings, 5- membered aromatic heterocyclyls containing 1 or 2 nitrogens fused to phenyl ring.
  • a bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; f) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; g) an oxazole ring fused to a 5- or 6-membered
  • bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) and imidazoimidazole (e.g. imidazo[1,2-a]imidazole).
  • imidazothiazole e.g. imidazo[2,1-b]thiazole
  • imidazoimidazole e.g. imidazo[1,2-a]imidazole
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g.
  • pyrazolo[1 ,5-a]pyrimidine benzodioxole and pyrazolopyridine (e.g. pyrazolo[1,5-a]pyridine) groups.
  • pyrazolopyridine groups e.g. pyrazolo[1,5-a]pyridine
  • a further example of a six membered ring fused to a five membered ring is a pyrrolopyridine group such as a pyrrolo[2,3-b]pyridine group.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
  • heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro- benzo[1,4]dioxine, benzo[1,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, indoiine, isoindoline and indane groups.
  • aromatic heterocyclyls fused to carbocyclic aromatic rings may therefore include but are not limited to benzothiophenyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, isobenzoxazoyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazinyl, phthalazinyl, carbolinyl and the like.
  • heterocycloalkyl or “non-aromatic heterocyclyl” encompasses optionally substituted saturated and unsaturated rings which contain at least one heteroatom such as N, S and O, or a heteromoiety such as O, S, S(O), SO2, N and NH.
  • the ring may contain 1, 2, 3, 4 or more heteroatoms or heteromoieties.
  • Cn1-n2 or “n1 to n2” this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1, 2, 3, 4 or more, of the ring atoms is replaced with a heteroatom or heteromoiety.
  • the ring may be a monocyclic ring or part of a polycyclic ring system.
  • Polycyclic ring systems include fused rings and spirocycles. Not every ring in a non-aromatic heterocyclic polycyclic ring system must contain a heteroatom, provided at least one ring contains one or more heteroatoms.
  • Non-aromatic heterocyclyls may be 3-8 membered mono-cyclic rings.
  • Examples of 5-membered non-aromatic heterocyclyl rings include 2H-pyrrolyl, 1pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, 2-pyrazolinyl, 3- pyrazolinyl, pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, imidazolidinyl, 3-dioxalanyl, thiazolidinyl, isoxazolidinyl, 2-imidazolinyl and the like.
  • 6-membered non-aromatic heterocyclyls include piperidinyl, piperidinonyl, pyranyl, dihyrdopyranyl, tetrahydropyranyl, 2H pyranyl, 4H pyranyl, thianyl, thianyl oxide, thianyl dioxide, piperazinyl, diozanyl, 1,4-dioxinyl, 1,4-dithianyl, 1,3,5triozalanyl, 1,3,5-trithianyl, 1,4-morpholinyl, thiomorpholinyl, 1,4-oxathianyl, triazinyl, 1,4thiazinyl and the like.
  • Non-aromatic heterocyclyls examples include azepanyl, oxepanyl, thiepanyl and the like.
  • Non-aromatic heterocyclyl rings may also be bicyclic heterocyclyl rings such as linked ring systems (for example uridinyl and the like) or fused ring systems.
  • Fused ring systems include non-aromatic 5-membered, 6-membered or 7-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like.
  • alkyleneheteroaryl refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component links the heteroaryl component to the point of attachment ⁇
  • the alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heteroaryl component and to the point of atachment. In some instances, the alkyl component can be absent.
  • the alkyl component can include any number of carbons, such as C1-6, C1-2, C1-3, C1-4, C1-5, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6.
  • the heteroaryl component is as defined herein. The numerical range from x to y in “Cx-y alkylenecycloalkyl” relates to the total number of alkyl carbons and heteroaryl ring atoms (carbon and heteroatoms together).
  • alkyleneheterocycloalkyl refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component links the heterocycloalkyl component to the point of attachment ⁇
  • the alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the heterocycloalkyl component and to the point of atachment. In some instances, the alkyl component can be absent.
  • the alkyl component can include any number of carbons, such as C1-6, C1-2, C1-3, C1-4, C1-5, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6.
  • the heterocycloalkyl component is as defined herein.
  • the numerical range from x to y in “Cx- y alkyleneheterocycloalkyl” relates to the total number of alkyl carbons and heterocycloalkyl ring atoms (carbon and heteroatoms together).
  • solvate refers to a complex of the compound and either stoichiometric or non-stoichiometric amounts of a solvent. Solvates are often formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • polymorph refers to the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.
  • the term “metabolite” refers to a derivative of a compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
  • Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • stereoisomer includes but is not limited to diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy– ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C14 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C
  • the compound of formula (I) is not one of the following: In some embodiments, one of X 2 , Z 1 , Z 2 , Z 3 and Z 4 is a heteroatom. The remainder will all denote a ring carbon atom as defined for each variable herein. In these embodiments, the 6,5-fused bicyclic core of the compounds of formula (I) possess 2 heteroatoms.
  • X 1 , X 2 , Z 1 , Z 2 , Z 3 and Z 4 are defined by embodiments 1-6: In some embodiments, X 1 , X 2 , Z 1 , Z 2 , Z 3 and Z 4 are according to any one of the above embodiments 1-4. In some embodiments, X 1 is NR 6 .
  • R 6 (if present) is H. In some embodiments, R 6 (if present) is C1-6alkyl, preferably C1-4alkyl. In some embodiments, X 1 is NR 6 and R 6 is H. In some embodiments, one of R 8 and R 9 (if present) is selected from halogen, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl and C1-6 haloalkyl, the other (if present) being hydrogen. In some embodiments, R 8 (if present) is selected from halogen, OR 13 , N(R 13 )2, SR 13 , C1- 6 alkyl and C1-6 haloalkyl, and R 9 (if present) is hydrogen.
  • R 9 (if present) is selected from halogen, OR 13 , N(R 13 )2, SR 13 , C1- 6 alkyl and C1-6 haloalkyl, and R 8 (if present) is hydrogen.
  • R 8 (if present) is selected from halogen, OR 13 and C1-6 alkyl, and R 9 (if present) is hydrogen.
  • R 9 (if present) is selected from halogen, OR 13 and C1-6 alkyl, and R 8 (if present) is hydrogen.
  • Z 1 is CR 8 .
  • Z 2 is CR 9 .
  • Z 1 is CR 8 and R 8 is selected from halogen, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl and C1-6 haloalkyl.
  • Z 2 is CR 9 and R 9 is selected from halogen, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl and C1-6 haloalkyl.
  • Z 1 is CR 8 and R 8 is selected from halogen, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl and C1-6 haloalkyl, and Z 2 is N or CH.
  • Z 2 is CR 9 and R 9 is selected from halogen, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl and C1-6 haloalkyl, and Z 1 is N or CH.
  • Z 3 is CR 10 , and preferably R 10 is H.
  • one of R 8 and R 9 is OR 13 .
  • one or both of Z 1 is CR 8 and/or Z 2 is CR 9 .
  • each R 13 (if present) is independently selected from hydrogen and C1-6 alkyl. In some embodiments, each R 13 (if present) is H.
  • each R 13 is C1-6alkyl, preferably C1-4alkyl, more preferably methyl.
  • X 2 is CR 7 .
  • R 7 (if present) is hydrogen.
  • Z 1 is CR 8 .
  • R 8 (if present) is hydrogen.
  • Z 2 is CR 9 .
  • R 9 (if present) is hydrogen.
  • Z 3 is CR 10 .
  • R 10 (if present) is hydrogen.
  • Z 4 is CR 11 .
  • R 11 (if present) is hydrogen.
  • R 7 , R 10 and R 11 (if present) are each hydrogen.
  • R 6 , R 7 , R 10 and R 11 are each hydrogen. In some embodiments, only one of R 8 , R 9 , R 10 and R 11 (if present) is other than hydrogen. In some embodiments, only R 8 of R 8 , R 9 , R 10 and R 11 (if present) is other than hydrogen. In some embodiments, only R 9 of R 8 , R 9 , R 10 and R 11 (if present) is other than hydrogen. In some embodiments, only R 10 of R 8 , R 9 , R 10 and R 11 (if present) is other than hydrogen. In some embodiments, only R 11 of R 8 , R 9 , R 10 and R 11 (if present) is other than hydrogen.
  • only one of R 6 , R 7 , R 8 , R 9 , R 10 and R 11 (if present) is other than hydrogen. In some embodiments, only R 6 of R 6 , R 7 , R 8 , R 9 , R 10 and R 11 (if present) is other than hydrogen. In some embodiments, only R 7 of R 6 , R 7 , R 8 , R 9 , R 10 and R 11 (if present) is other than hydrogen. In some embodiments, only R 8 of R 6 , R 7 , R 8 , R 9 , R 10 and R 11 (if present) is other than hydrogen.
  • R 9 of R 6 , R 7 , R 8 , R 9 , R 10 and R 11 is other than hydrogen.
  • only R 10 of R 6 , R 7 , R 8 , R 9 , R 10 and R 11 is other than hydrogen.
  • only R 11 of R 6 , R 7 , R 8 , R 9 , R 10 and R 11 is other than hydrogen.
  • at least one of R 1 and R 2 is not methyl. In some embodiments, both of R 1 and R 2 are not methyl.
  • the compound of formula (I) has the formula (II): wherein R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C14 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C
  • R 1 and R 2 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl and C4-14 alkylenecycloalkyl. In some embodiments, R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following:
  • R 1 and R 2 are combined with the atoms to which they are attached to form C3-6 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C 1- 8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N,
  • R 3 is hydrogen.
  • R 3 and one of R 1 and R 2 are combined with the atoms to which they are attached to form a C3-8 heterocycloalkyl, said C3-8 heterocycloalkyl being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1- 8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR 4
  • R 7 , R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(
  • R 7 , R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycl
  • R 7 , R 8 , R 9 , R 10 and R 11 when present are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and OR 13 wherein R 13 is selected from C 1-6 alkyl and C 1-6 haloalkyl, and the other of R 7 , R 8 R 9 , R 10 and R 11 are each hydrogen.
  • R 8 and R 9 when present are combined with the atoms to which they are each attached to form a C5-8 heterocycloalkyl or C5-10 heteroaryl, said C5-8 heterocycloalkyl and C5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: , wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached; said C5-8 heterocycloalkyl and C5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6 haloalkyl.
  • halogen O
  • CN CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6 hal
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: , wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached.
  • the compound of formula (I) has the formula (IIa): wherein R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C14 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C
  • R 1 and R 2 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl and C4-14 alkylenecycloalkyl. In some embodiments, R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following: ,
  • R 1 and R 2 are combined with the atoms to which they are attached to form C3-6 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C1- 8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S
  • R 3 is hydrogen.
  • R 3 and one of R 1 and R 2 are combined with the atoms to which they are attached to form a C3-8 heterocycloalkyl, said C3-8 heterocycloalkyl being further optionally substituted with a substituent selected from halogen, (O), CN, C 1-8 alkoxy, C 1 - 8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR 4
  • R 7 , R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)
  • R 7 , R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C 6 haloalkenyl, C 2 - 6 alkynyl, C 2 - 6 haloalkynyl, C 1 - 6 alkylamine, C 1 - 6 alkoxy, C 1 - 6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloal
  • R 7 , R 9 , R 10 and R 11 are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and OR 13 wherein R 13 is selected from C1-6 alkyl and C1-6 haloalkyl, and the other of R 7 , R 9 , R 10 and R 11 are each hydrogen.
  • the compound of formula (II) has the formula (IIb): wherein R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C 2 - 6 haloalkenyl, C 2 - 6 alkynyl, C 2 - 6 haloalkynyl, C 3 - 8 cycloalkyl, C 4-14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C14 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 al
  • R 1 and R 2 are each independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl and C4-14 alkylenecycloalkyl. In some embodiments, R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following: ,
  • R 1 and R 2 are combined with the atoms to which they are attached to form C3-6 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C1- 8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S
  • R 3 is hydrogen.
  • R 3 and one of R 1 and R 2 are combined with the atoms to which they are attached to form a C3-8 heterocycloalkyl, said C3-8 heterocycloalkyl being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1- 8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO 2 and NR 4
  • R 7 , R 8 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)
  • R 7 , R 8 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloal
  • R 7 , R 8 , R 10 and R 11 are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and OR 13 wherein R 13 is selected from C1-6 alkyl and C1-6 haloalkyl, and the other of R 7 , R 8 , R 10 and R 11 are each hydrogen.
  • the compound of formula (I) has the formula (IIc): wherein R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C14 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C 1-6 alkyl, C 1-6 haloalkyl, C 2 - 6 alkenyl, C 2 - 6 haloalkenyl, C 2 - 6 alkynyl, C 2 - 6 haloalkynyl, C3-8 cycloalkyl, C4
  • R 1 and R 2 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl and C4-14 alkylenecycloalkyl. In some embodiments, R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following: ,
  • R 1 and R 2 are combined with the atoms to which they are attached to form C3-6 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C1- 8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S
  • R 3 is hydrogen.
  • R 3 and one of R 1 and R 2 are combined with the atoms to which they are attached to form a C3-8 heterocycloalkyl, said C3-8 heterocycloalkyl being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1- 8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR 4
  • R 7 , R 8 , R 9 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C 6 haloalkenyl, C 2 - 6 alkynyl, C 2 - 6 haloalkynyl, C 1 - 6 alkylamine, C 1 - 6 alkoxy, C 1 - 6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP
  • R 7 , R 8 , R 9 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloal
  • R 7 , R 8 , R 9 and R 11 are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and OR 13 wherein R 13 is selected from C1-6 alkyl and C1-6 haloalkyl, and the other of R 7 , R 8 , R 9 and R 11 are each hydrogen.
  • the compound of formula (I) has the formula (IId): wherein R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C14 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl,
  • R 1 and R 2 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl and C4-14 alkylenecycloalkyl.
  • R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following:
  • R 1 and R 2 are combined with the atoms to which they are attached to form C3-6 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C1- 8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR 4 , wherein R 4 is defined as in any one of the foregoing paragraph
  • R 3 is hydrogen.
  • R 3 and one of R 1 and R 2 are combined with the atoms to which they are attached to form a C3-8 heterocycloalkyl, said C3-8 heterocycloalkyl being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1- 8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR 4
  • R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)
  • R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloal
  • R 7 , R 8 , R 9 and R 10 are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and OR 13 wherein R 13 is selected from C1-6 alkyl and C1-6 haloalkyl, and the other of R 7 , R 8 , R 9 and R 10 are each hydrogen.
  • the compound of formula (I) has the formula (III): wherein R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C14 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3
  • R 1 and R 2 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl and C4-14 alkylenecycloalkyl. In some embodiments, R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following:
  • R 1 and R 2 are combined with the atoms to which they are attached to form C3-6 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C 1- 8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N,
  • R 3 is hydrogen.
  • R 3 and one of R 1 and R 2 are combined with the atoms to which they are attached to form a C3-8 heterocycloalkyl, said C3-8 heterocycloalkyl being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1- 8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR 4
  • R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)
  • R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl
  • R 8 , R 9 , R 10 and R 11 when present are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and OR 13 wherein R 13 is selected from C 1-6 alkyl and C 1-6 haloalkyl, and the other of R 8 R 9 , R 10 and R 11 are each hydrogen.
  • R 8 and R 9 when present are combined with the atoms to which they are each attached to form a C5-8 heterocycloalkyl or C5-10 heteroaryl, said C5-8 heterocycloalkyl and C5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: , wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached; said C5-8 heterocycloalkyl and C5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6 haloalkyl.
  • halogen O
  • CN CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6 hal
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: , wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached.
  • the compound of formula (I) has the formula (IIIa): wherein R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C14 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C
  • R 1 and R 2 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl and C4-14 alkylenecycloalkyl. In some embodiments, R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following:
  • R 1 and R 2 are combined with the atoms to which they are attached to form C3-6 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C1- 8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N
  • R 3 is hydrogen.
  • R 3 and one of R 1 and R 2 are combined with the atoms to which they are attached to form a C3-8 heterocycloalkyl, said C3-8 heterocycloalkyl being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1- 8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR 4
  • R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C 6 haloalkenyl, C 2 - 6 alkynyl, C 2 - 6 haloalkynyl, C 1 - 6 alkylamine, C 1 - 6 alkoxy, C 1 - 6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP
  • R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl
  • R 8 , R 9 , R 10 and R 11 are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and OR 13 wherein R 13 is selected from C1-6 alkyl and C1-6 haloalkyl, and the other of R 8 R 9 , R 10 and R 11 are each hydrogen.
  • R 8 and R 9 are combined with the atoms to which they are each attached to form a C5-8 heterocycloalkyl or C5-10 heteroaryl, said C5-8 heterocycloalkyl and C5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from halogen,
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached; said C 5-8 heterocycloalkyl and C 5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6 haloalkyl.
  • halogen O
  • CN CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6 halo
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached.
  • the compound of formula (I) has the formula (IV): wherein X2 is O or S, R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C14 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylene
  • R 1 and R 2 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl and C4-14 alkylenecycloalkyl.
  • R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following:
  • R 1 and R 2 are combined with the atoms to which they are attached to form C3-6 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C1- 8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR 4 , wherein R 4 is defined as in any one of the foregoing paragraph
  • R 3 is hydrogen.
  • R 3 and one of R 1 and R 2 are combined with the atoms to which they are attached to form a C3-8 heterocycloalkyl, said C3-8 heterocycloalkyl being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1- 8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR 4
  • R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)
  • R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloal
  • R 8 , R 9 , R 10 and R 11 when present are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and OR 13 wherein R 13 is selected from C1-6 alkyl and C1-6 haloalkyl, and the other of R 8 R 9 , R 10 and R 11 are each hydrogen.
  • R 8 and R 9 when present are combined with the atoms to which they are each attached to form a C5-8 heterocycloalkyl or C5-10 heteroaryl, said C5-8 heterocycloalkyl and C5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: , wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached; said C5-8 heterocycloalkyl and C5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO 2 CH 3, SOCH 3 , C 1-6 alkyl and C 1-6 haloalkyl.
  • halogen O
  • CN CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO 2 CH 3, SOCH 3 , C 1-6 al
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached.
  • X 2 is O.
  • the compound of formula (I) has the formula (IVa): wherein R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C14 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C
  • R 1 and R 2 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl and C4-14 alkylenecycloalkyl. In some embodiments, R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following: ,
  • R 1 and R 2 are combined with the atoms to which they are attached to form C3-6 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C1- 8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S
  • R 3 is hydrogen.
  • R 3 and one of R 1 and R 2 are combined with the atoms to which they are attached to form a C3-8 heterocycloalkyl, said C3-8 heterocycloalkyl being further optionally substituted with a substituent selected from halogen, (O), CN, C 1-8 alkoxy, C 1 - 8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR 4
  • R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)
  • R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C 6 haloalkenyl, C 2 - 6 alkynyl, C 2 - 6 haloalkynyl, C 1 - 6 alkylamine, C 1 - 6 alkoxy, C 1 - 6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C
  • R 8 , R 9 , R 10 and R 11 are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and OR 13 wherein R 13 is selected from C1-6 alkyl and C1-6 haloalkyl, and the other of R 8 R 9 , R 10 and R 11 are each hydrogen.
  • R 8 and R 9 are combined with the atoms to which they are each attached to form a C5-8 heterocycloalkyl or C5-10 heteroaryl, said C5-8 heterocycloalkyl and C5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from halogen,
  • R 8 and R 9 are combined to form a C 5-8 heterocycloalkyl or C 5-10 heteroaryl selected from the following: , wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached; said C 5-8 heterocycloalkyl and C 5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6 haloalkyl.
  • halogen O
  • CN CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: , wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached.
  • the compound of formula (I) has the formula (V): wherein R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C 3 -C 8 heterocycloalkyl, C 4 -C 14 alkyleneheterocycloalkyl, C 6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl,
  • R 1 and R 2 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl and C4-14 alkylenecycloalkyl. In some embodiments, R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following:
  • R 1 and R 2 are combined with the atoms to which they are attached to form C3-6 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C1- 8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N
  • R 3 is hydrogen.
  • R 3 and one of R 1 and R 2 are combined with the atoms to which they are attached to form a C3-8 heterocycloalkyl, said C3-8 heterocycloalkyl being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1- 8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR 4
  • R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C 6 haloalkenyl, C 2 - 6 alkynyl, C 2 - 6 haloalkynyl, C 1 - 6 alkylamine, C 1 - 6 alkoxy, C 1 - 6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP
  • R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloal
  • R 8 , R 9 , R 10 and R 11 when present are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and OR 13 wherein R 13 is selected from C1-6 alkyl and C1-6 haloalkyl, and the other of R 8 R 9 , R 10 and R 11 are each hydrogen.
  • R 8 and R 9 when present are combined with the atoms to which they are each attached to form a C5-8 heterocycloalkyl or C5-10 heteroaryl, said C5-8 heterocycloalkyl and C5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached; said C 5-8 heterocycloalkyl and C 5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6 haloalkyl.
  • halogen O
  • CN CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6 halo
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: , wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached.
  • the compound of formula (I) has the formula (Va): wherein R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C14 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl, C4-14 alkylenecycloalkyl, C
  • R 1 and R 2 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl and C4-14 alkylenecycloalkyl. In some embodiments, R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following: ,
  • R 1 and R 2 are combined with the atoms to which they are attached to form C3-6 heterocycloalkyl, said C3-6 heterocycloalkyl being optionally substituted with one or more substituents independently selected from halogen, CN, C1- 8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S
  • R 3 is hydrogen.
  • R 3 and one of R 1 and R 2 are combined with the atoms to which they are attached to form a C3-8 heterocycloalkyl, said C3-8 heterocycloalkyl being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1- 8 alkylamino, C1-8 alkylsulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from O, S, N, S(O), SO2 and NR 4
  • R 8 , R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)
  • R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2- C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1-6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1- 6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alkyleneheterocycloalkyl
  • R 8 , R 9 , R 10 and R 11 are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and OR 13 wherein R 13 is selected from C1-6 alkyl and C1-6 haloalkyl, and the other of R 8 R 9 , R 10 and R 11 are each hydrogen.
  • R 8 and R 9 are combined with the atoms to which they are each attached to form a C5-8 heterocycloalkyl or C5-10 heteroaryl, said C5-8 heterocycloalkyl and C 5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, C1-8 alkoxy, C1-8 alkylamino, C1-8 alkylsulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl including 1 or 2 ring heteromoieties selected from halogen,
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: , wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached; said C5-8 heterocycloalkyl and C5-10 heteroaryl each being further optionally substituted with a substituent selected from halogen, (O), CN, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6 haloalkyl.
  • halogen O
  • CN CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C1-6 alkyl and C1-6 hal
  • R 8 and R 9 are combined to form a C5-8 heterocycloalkyl or C5-10 heteroaryl selected from the following: , wherein the dashed bond denotes the bond shared with the aromatic ring to which R 8 and R 9 are attached.
  • the compound of formula (I) is a compound of formula (IIaa) wherein L, R 1 , R 2 , R 3 and R 9 are as defined for any aspect or embodiment herein. In some embodiments of the compounds of formula (IIaa), one or both of R 1 and R 2 is not methyl.
  • the compound of formula (I) is a compound of formula (IIba) wherein L, R 1 , R 2 , R 3 and R 8 are as defined for any aspect or embodiment herein.
  • the compound of formula (I) is a compound of formula (IIda) wherein L, R 1 , R 2 , R 3 , R 8 and R 9 are as defined for any aspect or embodiment herein.
  • the compound of formula (I) is a compound of formula (IIIb) wherein L, R 1 , R 2 , R 3 , R 8 and R 9 are as defined for any aspect or embodiment herein.
  • the compound of formula (I) is a compound of formula (IIaa) wherein R 1 , R 2 , and R 9 are as defined for any aspect or embodiment herein. In some embodiments of the compounds of formula (IIaa), one or both of R 1 and R 2 is not methyl. In some embodiments, the compound of formula (I) is a compound of formula (IIbb) wherein R 1 , R 2 and R 8 are as defined for any aspect or embodiment herein. In some embodiments, the compound of formula (I) is a compound of formula (IIdb) wherein R 1 , R 2 , R 8 and R 9 are as defined for any aspect or embodiment herein.
  • the compound of formula (I) is a compound of formula (IIIc) wherein R 1 , R 2 , R 8 and R 9 are as defined for any aspect or embodiment herein.
  • R 1 , R 2 , R 8 and R 9 are as defined for any aspect or embodiment herein.
  • the compound is not one of the following: .
  • the compound of any of formulae (I), (II), (IIa), (IIaa), (IIab), (IIb), (IIba), (IIbb), (IIc), (IId), (IIda), (IIdb), (III), (IIIa), (IIIb), (IIIc) (IV), (IVa), (V) and (Va) may be selected from compounds P-1 to P-56. In some embodiments, the compound is selected from P-13, P-20, P-21, P-37 and P-45.
  • inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
  • the invention includes all crystalline forms of a compound of Formula (I) including anhydrous crystalline forms, hydrates, solvates and mixed solvates. If any of these crystalline forms demonstrates polymorphism, all polymorphs are within the scope of this invention.
  • Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds.
  • Formula (I) includes compounds having the indicated structures, including the hydrated or solvated forms, as well as the non-hydrated and non-solvated forms.
  • the compounds of Formula (I) or salts, tautomers, N-oxides, polymorphs or prodrugs thereof may be provided in the form of solvates.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, alcohols such as methanol, ethanol or isopropyl alcohol, DMSO, acetonitrile, dimethyl formamide (DMF), acetic acid, and the like with the solvate forming part of the crystal lattice by either non-covalent binding or by occupying a hole in the crystal lattice. Hydrates are formed when the solvent is water, alcoholates are formed when the solvent is alcohol.
  • Solvates of the compounds of the present invention can be conveniently prepared or formed during the processes described herein. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the invention.
  • Basic nitrogen-containing groups may be quarternised with such agents as C1-6alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others. Nitrogen containing groups may also be oxidised to form an N-oxide.
  • the compound of Formula (I) or salts, tautomers, N-oxides, solvates and/or prodrugs thereof that form crystalline solids may demonstrate polymorphism.
  • the compound of Formula (I) may demonstrate tautomerism. Tautomers are two interchangeable forms of a molecule that typically exist within an equilibrium. Any tautomers of the compounds of Formula (I) are to be understood as being within the scope of the invention.
  • the compound of Formula (I) may contain one or more stereocentres. All stereoisomers of the compounds of formula (I) are within the scope of the invention. Stereoisomers include enantiomers, diastereomers, geometric isomers (E and Z olephinic forms and cis and trans substitution patterns) and atropisomers.
  • the compound is a stereoisomerically enriched form of the compound of formula (I) at any stereocentre.
  • the compound may be enriched in one stereoisomer over another by at least about 60, 70, 80, 90, 95, 98 or 99%.
  • the compound of Formula (I) or its salts, tautomers, solvates, N-oxides, and/or stereoisomers may be isotopically enriched with one or more of the isotopes of the atoms present in the compound.
  • the compound may be enriched with one or more of the following minor isotopes: 2 H, 3 H, 13 C, 14 C, 15 N and/or 17 O, preferably 2 H.
  • An isotope may be considered enriched when its abundance is greater than its natural abundance.
  • a "prodrug” is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce a compound of formula (I) provided herein.
  • a prodrug may be an acylated derivative of a compound as provided herein.
  • Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively.
  • prodrugs examples include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
  • Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined to free amino, and amido groups of compounds of Formula (I).
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3- methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of Formula (I) through the carbonyl carbon prodrug sidechain.
  • Compositions, formulations and modes of administration The compounds of formula (I) can be administered alone or in the form of a pharmaceutical composition.
  • the compounds of formula (I) are usually administered in the form of pharmaceutical compositions, that is, in admixture with at least one pharmaceutically acceptable excipient.
  • the proportion and nature of any pharmaceutically acceptable excipient(s) are determined by the properties of the selected compound of the invention, the chosen route of administration, and standard pharmaceutical practice.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions of the disclosure typically include a therapeutically effective amount of one or more active ingredients in admixture with one or more pharmaceutically and physiologically acceptable formulation materials.
  • Suitable formulation materials include, but are not limited to, antioxidants, preservatives, coloring, flavoring and diluting agents, emulsifying agents, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, diluents, excipients and/or pharmaceutical adjuvants.
  • a suitable vehicle may be water for injection, physiological saline solution, or artificial perilymph, possibly supplemented with other materials common in compositions for parenteral administration.
  • Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.
  • compositions of the present disclosure additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure.
  • materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatine; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminium hydroxide; alginic acid; pyrogenfree water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as
  • Various dosage units are each preferably provided as a discrete dosage tablet, capsules, lozenge, dragee, gum, or other type of solid formulation.
  • Capsules may encapsulate a powder, liquid, or gel.
  • the solid formulation may be swallowed, or may be of a suckable or chewable type (either frangible or gum-like).
  • the present invention contemplates dosage unit retaining devices other than blister packs; for example, packages such as bottles, tubes, canisters, packets.
  • the dosage units may further include conventional excipients well-known in pharmaceutical formulation practice, such as binding agents, gellants, fillers, tableting lubricants, disintegrants, surfactants, and colorants; and for suckable or chewable formulations.
  • a compound of formula (I) may be administered in any form and route which makes the compound bioavailable.
  • Compositions described herein may be administered systemically or directly to the site of condition or disease.
  • Compositions described herein may be formulated from compounds according to Formula (I) for any appropriate route of administration including, for example, oral, rectal, nasal, vaginal, topical (including transdermal, buccal, ocular and sublingual), parenteral (including subcutaneous, intraperitoneal, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, intracisternal injection as well as any other similar injection or infusion techniques), inhalation, insufflation, infusion or implantation techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).
  • compositions described herein may be administered orally, nasally, intravenously, intramuscularly, topically, subcutaneously, rectally, vaginally or by urethral application.
  • Compositions intended for oral use may further comprise one or more components such as sweetening agents, flavouring agents, colouring agents and/or preserving agents in order to provide appealing and palatable preparations.
  • Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatine or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavouring agents may be added to provide palatable oral preparations.
  • Such suspensions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavouring and colouring agents, may also be present.
  • Pharmaceutical compositions may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive oil or arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents include naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides such as sorbitan monoleate, and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide such as polyoxyethylene sorbitan monoleate.
  • An emulsion may also comprise one or more sweetening and/or flavouring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such Formulations may also comprise one or more demulcents, preservatives, flavouring agents and/or colouring agents.
  • a composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials. Examples of such components are described in Martindale – The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences.
  • Formulations may comprise microcapsules, such as hydroxymethylcellulose or gelatine-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.
  • Preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl gallate.
  • Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerine, propylene glycol, and butylene glycol.
  • Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils.
  • Suitable fragrances and colours include, but are not limited to, FD&C Red No.40 and FD&C Yellow No.5.
  • Suitable additional ingredients that may be included in a topical Formulation include, but are not limited to, abrasives, absorbents, anticaking agents, antifoaming agents, antistatic agents, astringents (such as witch hazel), alcohol and herbal extracts such as chamomile extract, binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzy
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P.
  • injectables can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • a pharmaceutical composition may be formulated as inhaled formulations, including sprays, mists, or aerosols.
  • the composition or combination provided herein may be delivered via any inhalation methods known to a person skilled in the art.
  • inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable.
  • propellants such as CFC or HFA
  • propellants such as CFC or HFA
  • Other suitable devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers.
  • Aerosol formulations for use in the subject method typically include propellants, surfactants and co-solvents and may be filled into conventional aerosol containers that are closed by a suitable metering valve.
  • Inhalant compositions may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses.
  • Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent such as isotonic saline or bacteriostatic water.
  • the solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs.
  • Suitable Formulations wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • Compositions suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by at least partially dispersing the active in one or more lipophilic bases and then shaping the mixture.
  • Pharmaceutical compositions may be formulated as sustained release formulations such as a capsule that creates a slow release of active following administration.
  • Such formulations may generally be prepared using well-known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Carriers for use within such formulations are biocompatible, and may also be biodegradable.
  • the formulation provides a relatively constant level of active release.
  • the amount of active contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated.
  • One skilled in the art can readily select the proper form and route of administration depending on the particular characteristics of the compound selected, the disease or condition to be treated, the stage of the disease or condition, and other relevant circumstances. It will be understood, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, number of doses, and rate of excretion, drug combination (i.e.
  • a therapeutically effective amount generally refers to an amount of one or more active ingredients of the invention that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more sign or symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more sign or symptoms of the particular disease, condition, or disorder described herein.
  • a therapeutically effective dosage is formulated to contain a concentration (by weight) of at least about 0.1% up to about 50% or more, and all combinations and sub- combinations of ranges therein.
  • compositions can be formulated to contain one or more actives described herein in a concentration of from about 0.1 to less than about 50%, for example, about 49, 48, 47, 46, 45, 44, 43, 42, 41 or 40%, with concentrations of from greater than about 0.1%, for example, about 0.2, 0.3, 0.4 or 0.5%, to less than about 40%, for example, about 39, 38, 37, 36, 35, 34, 33, 32, 31 or 30%.
  • compositions may contain from about 0.5% to less than about 30%, for example, about 29, 28, 27, 26, 25, 25, 24, 23, 22, 21 or 20%, with concentrations of from greater than about 0.5%, for example, about 0.6, 0.7, 0.8, 0.9 or 1%, to less than about 20%, for example, about 19, 18, 17, 16, 15, 14, 13, 12, 11 or 10%.
  • the compositions can contain from greater than about 1% for example, about 2%, to less than about 10%, for example about 9 or 8%, including concentrations of greater than about 2%, for example, about 3 or 4%, to less than about 8%, for example, about 7 or 6%.
  • the active agent can, for example, be present in a concentration of about 5%.
  • the pharmaceutical composition comprises a compound according to any one of the herein disclosed embodiments, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof, an additional therapeutic agent, and a pharmaceutically acceptable excipient.
  • the additional agent may be any suitable agent described herein.
  • the additional agent is a psychoactive drug, including those described herein.
  • the additional agent is useful for treatment of a disease, disorder or condition by activation of a serotonin receptor, including those described herein.
  • the additional agent is selected from any one of the following, including those described herein: an agent for a mental illness and/or a neuropsychiatric condition; an agent for psychosis and/or psychotic symptoms; an agent for attention deficit hyperactivity disorder and/or attention deficit disorder; an agent for dementia and/or Alzheimer’s disease; and an agent for an addiction disorder.
  • the present disclosure also provides methods of delivering to a subject in need thereof a compound of formula (I) or a composition (e.g., an effective amount of the compound or composition) of the present disclosure.
  • the present disclosure provides methods of treating a disease in a subject in need thereof comprising administering to the subject in need thereof an effective amount (e.g., therapeutically effective amount) of a compound or composition (e.g., pharmaceutical composition) of the present disclosure.
  • the present disclosure provides methods of preventing a disease in a subject in need thereof comprising administering to the subject in need thereof an effective amount (e.g., therapeutically effective amount) of a compound of formula (I) or composition (e.g., pharmaceutical composition) of the present disclosure.
  • a method e.g., method of delivering an active agent to a subject in need thereof, method of treating a disease in a subject in need thereof, method of preventing a disease in a subject in need thereof
  • uses of the compounds of formula (I) or compositions of the present disclosure in a method e.g., method of delivering an active agent to a subject in need thereof, method of treating a disease in a subject in need thereof, method of preventing a disease in a subject in need thereof
  • the effective amount is effective in treating the disease.
  • the effective amount is effective in preventing the disease.
  • the present disclosure provides a method of treating a disease, disorder or condition by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein.
  • the present disclosure provides a method of preventing a disease, disorder or condition by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein.
  • the present disclosure provides method of treating a disease, disorder or condition by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein, in combination with another known agent useful for treatment of a disease, disorder or condition by activation of a serotonin receptor.
  • the other known agents useful for treatment of a disease, disorder or condition by activation of a serotonin receptor may be any suitable agents known in the art, including those described herein.
  • the present disclosure provides method of preventing a disease, disorder or condition by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein, in combination with another known agent useful for prevention of a disease, disorder or condition by activation of a serotonin receptor.
  • the serotonin receptor is 5-HT2A.
  • the serotonin receptor is one or both of 5-HT2A and 5-HT2C. Additionally, or alternatively, in some embodiments, the serotonin receptor is not 5- HT2B.
  • the compound of formula (I) of the present disclosure is selective towards the 5-HT2A receptor over one or both of the 5-HT2C receptor and the 5-HT2B receptor, preferably over the 5-HT2B receptor. In some embodiments, the compound of formula (I) is selective towards the 5-HT2C receptor over one or both of the 5-HT2A receptor and the 5-HT2B receptor, preferably over the 5-HT2B receptor. In some embodiments, the compound of formula (I) is selective toward the 5-HT2A receptor and 5-HT2C receptor over the 5-HT2B receptor.
  • the compound of formula (I) of the present disclosure exhibits an EC50 value for the 5-HT2A receptor of less than about 1 mM, less than about 100 ⁇ M, less than about 10 ⁇ M, less than about 1 ⁇ M, or less than about 100 nM, or less than about 10 nM, as determined by an assay described herein, for example an assay of calcium flux activity such as measuring changes in intracellular calcium.
  • the compound of formula (I) exhibits an EC50 for the 5-HT2A receptor of less than about 1 mM, less than about 900 ⁇ M, less than about 800 ⁇ M, less than about 700 ⁇ M, less than about 600 ⁇ M, less than about 500 ⁇ M, less than about 400 ⁇ M, less than about 300 ⁇ M, less than about 200 ⁇ M, less than about 100 ⁇ M, less than about 90 ⁇ M, less than about 80 ⁇ M, less than about 70 ⁇ M, less than about 60 ⁇ M, less than about 50 ⁇ M, less than about 40 ⁇ M, less than about 30 ⁇ M, less than about 20 ⁇ M, less than about 10 ⁇ M, less than about 9 ⁇ M, less than about 8 ⁇ M, less than about 7 ⁇ M, less than about 6 ⁇ M, less than about 5 ⁇ M, less than about 4 ⁇ M, less than about 3 ⁇ M, less than about 2 ⁇ M, less than about 1 ⁇ M, less than about
  • the compound of formula (I) of the present disclosure exhibits an EC50 value for the 5-HT2C receptor of less than about 1 mM, less than about 100 ⁇ M, less than about 10 ⁇ M, less than about 1 ⁇ M, or less than about 100 nM, or less than about 10 nM, as determined by an assay described herein, for example an assay of calcium flux activity such as measuring changes in intracellular calcium.
  • the compound of formula (I) exhibits an EC50 for the 5-HT2C receptor of less than about 1 mM, less than about 900 ⁇ M, less than about 800 ⁇ M, less than about 700 ⁇ M, less than about 600 ⁇ M, less than about 500 ⁇ M, less than about 400 ⁇ M, less than about 300 ⁇ M, less than about 200 ⁇ M, less than about 100 ⁇ M, less than about 90 ⁇ M, less than about 80 ⁇ M, less than about 70 ⁇ M, less than about 60 ⁇ M, less than about 50 ⁇ M, less than about 40 ⁇ M, less than about 30 ⁇ M, less than about 20 ⁇ M, less than about 10 ⁇ M, less than about 9 ⁇ M, less than about 8 ⁇ M, less than about 7 ⁇ M, less than about 6 ⁇ M, less than about 5 ⁇ M, less than about 4 ⁇ M, less than about 3 ⁇ M, less than about 2 ⁇ M, less than about 1 ⁇ M, less than about
  • the compound of formula (I) of the present disclosure exhibits an EC50 value for the 5-HT2B receptor of greater than about 1 ⁇ M, greater than about 10 ⁇ M, or greater than about 100 ⁇ M, as determined by an assay described herein, for example an assay of calcium flux activity such as measuring changes in intracellular calcium.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is a mental illness or a neuropsychiatric condition.
  • the present application also includes a method of treating a mental illness or a neuropsychiatric condition comprising administering to a subject in need thereof a compound of formula (I) or a composition as described herein.
  • the present application also includes a use of a compound of formula (I) of the present disclosure for treatment of a mental illness or a neuropsychiatric condition, as well as a use of a compound of formula (I) of the present disclosure for the preparation of a medicament for treatment of a mental illness or a neuropsychiatric condition.
  • the application further includes a compound of formula (I) of the present disclosure for use in treating a mental illness or a neuropsychiatric condition.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is a mental illness or a neuropsychiatric condition and compound of formula (I) of the present disclosure is administered in combination with one or more additional agents for a mental illness or a neuropsychiatric condition.
  • the one or more additional agents for a mental illness or a neuropsychiatric condition may be any suitable agents known in the art, including those described herein.
  • the additional agents for a mental illness or a neuropsychiatric condition is selected from antipsychotics, including typical antipsychotics and atypical antipsychotics; antidepressants including selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs) (e.g.
  • bupropion anti-anxiety medication including benzodiazepines such as alprazolam; agents for an addiction disorder such as alcohol addiction (e.g., disulfiram), nicotine dependence (e.g., varenicline) and opioid use disorder (e.g., methadone, buprenorphine, buprenorphine-naloxone and buprenorphine long-acting injection); mood stabilizers such as lithium and anticonvulsants such carbamazepine, divalproex (valproic acid), lamotrigine, gabapentin and topiramate.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is neurodegeneration.
  • the present application also includes a method of treating neurodegeneration comprising administering to a subject in need thereof a compound of formula (I) or a composition as described herein.
  • the present application also includes a use of a compound of formula (I) of the present disclosure for treatment of neurodegeneration, as well as a use of a compound of formula (I) of the present disclosure for the preparation of a medicament for treatment neurodegeneration.
  • the application further includes a compound of formula (I) of the present disclosure for use in treating neurodegeneration.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is reduced brain- derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR) activation and/or inflammation.
  • BDNF brain- derived neurotrophic factor
  • mTOR mammalian target of rapamycin
  • the disease, disorder or condition that is treated by activation of a serotonin receptor comprises cognitive impairment; ischemia including stroke; neurodegeneration; refractory substance use disorders; sleep disorders; pain, such as social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, nerve pain, referred pain, phantom pain, neuropathic pain, cluster headaches and migraine; obesity and eating disorders; epilepsies and seizure disorders; neuronal cell death; excitotoxic cell death; or a combination thereof.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is psychosis or psychotic symptoms.
  • the present application also includes a method of treating psychosis or psychotic symptoms comprising administering to a subject in need thereof a compound of formula (I) or a composition as described herein.
  • the present application also includes a use of a compound of formula (I) of the present disclosure for treatment of psychosis or psychotic symptoms, as well as a use of a compound of formula (I) of the present disclosure for the preparation of a medicament for treatment of psychosis or psychotic symptoms.
  • the application further includes a compound of formula (I) of the present disclosure for use in treating psychosis or psychotic symptoms.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is psychosis or psychotic symptoms and the the compound of formula (I) of the present disclosure is administered in combination with one or more additional agents for psychosis or psychotic symptoms.
  • the one or more additional agents for psychosis or psychotic symptoms may be any suitable agents known in the art, including those described herein.
  • the additional agents for psychosis or psychotic symptoms are selected typical antipsychotics and atypical antipsychotics.
  • the typical antipsychotics may be selected from acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carfenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, dixyrazine, droperidol, fluanisone, flupentixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, metitepine, molindone, moperone, oxypertine, oxyprotepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, piperacetazine, pipotiazine, prochlorperazine, promazine, prothipendyl, spiperone, s
  • the atypical antipsychotics may be selected from amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, clorotepine, clotiapine, clozapine, iloperidone, levosulpiride, lurasidone, melperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidone and zotepine, and combinations thereof.
  • administering to said subject in need thereof a therapeutically effective amount of the compound of formula (I) of the present disclosure does not result in a worsening of psychosis or psychotic symptoms such as, but not limited to, hallucinations and delusions.
  • administering to said subject in need thereof a therapeutically effective amount of the compound of formula (I) results in an improvement of psychosis or psychotic symptoms such as, but not limited to, hallucinations and delusions.
  • administering to said subject in need thereof a therapeutically effective amount of the compounds of formula (I) results in an improvement of psychosis or psychotic symptoms.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is a central nervous system (CNS) disease, disorder or condition and/or a neurological disease, disorder or condition.
  • CNS central nervous system
  • the present application also includes a method of treating a CNS disease, disorder or condition and/or a neurological disease, disorder or condition comprising administering a therapeutically effective amount of compound of formula (I) or a composition of the present disclosure to a subject in need thereof.
  • the present application also includes a use of compound of formula (I) of the present disclosure for treatment a CNS disease, disorder or condition and/or a neurological disease, disorder or condition, as well as a use of compound of formula (I) of the present disclosure for the preparation of a medicament for treatment of a CNS disease, disorder or condition and/or a neurological disease, disorder or condition.
  • the application further includes a compound of formula (I) of the present disclosure of the application for use in treating a CNS disease, disorder or condition and/or a neurological disease, disorder or condition.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is a central nervous system (CNS) disease, disorder or condition and/or a neurological disease, disorder or condition and the compound of formula (I) of the present disclosure is administered in combination with one or more additional agents for a central nervous system (CNS) disease, disorder or condition and/or a neurological disease, disorder or condition.
  • the one or more additional agents for a central nervous system (CNS) disease, disorder or condition and/or a neurological disease, disorder or condition may be any suitable agents known in the art, including those described herein.
  • the additional agents for a central nervous system (CNS) disease, disorder or condition and/or a neurological disease, disorder or condition are selected from lithium, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof.
  • CNS central nervous system
  • Non limiting examples of standard of care therapy for depression are sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole.
  • Non-limiting examples of standard of care therapy for depression are citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is selected from attention deficit hyperactivity disorder and attention deficit disorder and a combination thereof.
  • the present application also includes a method of treating attention deficit hyperactivity disorder and/or attention deficit disorder comprising administering to a subject in need thereof a compound of formula (I) or a composition as described herein.
  • the present application also includes a use of a compound of formula (I) of the present disclosure for treatment of attention deficit hyperactivity disorder and/or attention deficit disorder, as well as a use of a compound of formula (I) of the present disclosure for the preparation of a medicament for treatment of attention deficit hyperactivity disorder and/or attention deficit disorder.
  • the application further includes a compound of formula (I) of the present disclosure for use in treating attention deficit hyperactivity disorder and/or attention deficit disorder.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is attention deficit hyperactivity disorder and/or attention deficit disorder and a combination thereof and the compound of formula (I) of the present disclosure is administered in combination with one or more additional agents for attention deficit hyperactivity disorder and/or attention deficit disorder and a combination thereof.
  • the one or more additional agents for attention deficit hyperactivity disorder and/or attention deficit disorder may be any suitable agents known in the art, including those described herein.
  • the additional agents for attention deficit hyperactivity disorder and/or attention deficit disorder and a combination thereof are selected from methylphenidate, dexamphetamine, lisdexamfetine, atomoxetine and amphetamine and a combination thereof.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is selected from dementia and Alzheimer’s disease and a combination thereof. Accordingly, the present application also includes a method of treating dementia and/or Alzheimer’s disease comprising administering to a subject in need thereof a compound of formula (I) or a composition as described herein.
  • the present application also includes a use of a compound of formula (I) of the present disclosure for treatment of dementia and/or Alzheimer’s disease, as well as a use of a compound of formula (I) of the present disclosure for the preparation of a medicament for treatment of dementia and/or Alzheimer’s disease.
  • the application further includes a compound of formula (I) of the present disclosure for use in treating dementia and/or Alzheimer’s disease.
  • the disease, disorder or condition that is treated by activation of a serotonin receptor is dementia or Alzheimer’s disease and the compound of formula (I) of the present disclosure is administered in combination with one or more additional agents for dementia or Alzheimer’s disease.
  • the one or more additional agents for dementia or Alzheimer’s disease may be any suitable agents known in the art, including those described herein.
  • the additional agents for dementia and Alzheimer’s disease are selected from acetylcholinesterase inhibitors, NMDA antagonists and nicotinic agonists.
  • the acetylcholinesterase inhibitors may be selected from donepezil, galantamine, rivastigmine, and phenserine, and combinations thereof.
  • the NMDA antagonists may be selected from MK-801, ketamine, phencyclidine, and memantine, and combinations thereof.
  • the nicotinic agonists may be selected from nicotine, nicotinic acid, nicotinic alpha7 agonists, or alpha2 beta4 agonists or a combination thereof.
  • the present disclosure provides a method of treating a mental illness, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein.
  • the present disclosure provides a method of preventing a mental illness, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein.
  • the mental illness may be a neuropsychiatric condition.
  • the mental illness is selected from anxiety disorders such as generalized anxiety disorder, panic disorder, social anxiety disorder and specific phobias; depression such as, hopelessness, loss of pleasure, fatigue and suicidal thoughts; mood disorders, such as depression, bipolar disorder, cancer-related depression, anxiety and cyclothymic disorder; psychotic disorders, such as hallucinations, delusions, mania, schizophrenia, schizoaffective disorder, schizophreniform Disorder; impulse control and addiction disorders, such as pyromania (starting fires), kleptomania (stealing) and compulsive gambling; alcohol addiction; drug addiction, such as opioid addiction/dependence, nicotine dependence, cocaine dependence, marijuana abuse and so on; smoking cessation; personality disorders, such as antisocial personality disorder, aggression, obsessive-compulsive personality disorder and paranoid personality disorder; obsessive-compulsive disorder (OCD), such as thoughts or fears that cause a subject to perform certain rituals or routines; post- traumatic stress disorder (PTSD); stress response syndrome
  • anxiety disorders
  • the mental illness is selected from hallucinations and delusions and a combination thereof.
  • the hallucinations may be selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations and chronoceptive hallucinations, and a combination thereof.
  • the present disclosure provides a method for treating a central nervous system (CNS) disease, disorder or condition and/or a neurological disease, disorder or condition, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein.
  • the present disclosure provides a method for preventing a central nervous system (CNS) disease, disorder or condition and/or a neurological disease, disorder or condition, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition as described herein.
  • the CNS disease, disorder or condition and/or neurological disease, disorder or condition is selected from neurological diseases including neurodevelopmental diseases and neurodegenerative diseases such as Alzheimer’s disease; presenile dementia; senile dementia; vascular dementia; Lewy body dementia; cognitive impairment, Parkinson’s disease and Parkinsonian related disorders such as Parkinson dementia, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infections; CNS inflammation; stroke; multiple sclerosis; Huntington’s disease; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; hereditary ataxias; neuro-otological and eye movement disorders; neurodegenerative diseases of the retina amyotrophic lateral sclerosis; tardive dyskinesias; hyperkinetic disorders; attention deficit hyperactivity disorder and attention deficit disorders; restless leg syndrome; Tourette's syndrome; Tic disorder; schizophrenia; autism spectrum disorders; tuberous sclerosis; Rett syndrome; cerebral palsy; disorders of the reward system including eating disorders such as anorexia
  • the present disclosure provides a method for increasing neuronal plasticity, the method comprising contacting a neuronal cell with a compound of formula (I) or a pharmaceutical composition as described herein, in an amount sufficient to increase neuronal plasticity of the neuronal cell.
  • Neuronal plasticity refers to the ability of the brain to change its structure and/or function continuously throughout a subject’s life. Examples of the changes to the brain include, but are not limited to, the ability to adapt or respond to internal and/or external stimuli, such as due to an injury, and the ability to produce new neurites, dendritic spines, and synapses.
  • Increasing neuronal plasticity includes, but is not limited to, promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, increasing dendritic spine density, and increasing excitatory synapsis in the brain.
  • increasing neuronal plasticity comprises promoting neuronal growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arbor complexity, and increasing dendritic spine density.
  • increasing neuronal plasticity can treat neurodegenerative disorder, Alzheimer’s, Parkinson’s disease, psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder.
  • the present disclosure provides methods of treating weight, comprising administering an effective amount of a compound of the invention to a subject in need thereof.
  • Treatment of weight may include treating weight gain; weight loss; metabolic disorder; weight gain associated with pharmaceutical intervention; weight gain associated with a mental illness (including those described herein); eating disorders such as anorexia, bulimia, cachexia, etc.; eating behaviour; obesity; diabetes; insulin resistance; pre-diabetes; glucose intolerance; hyperlipidemia; and cardiovascular disease.
  • the present disclosure provides a method for increasing dendritic spine density, the method comprising contacting a neuronal cell with a compound of formula (I) or a pharmaceutical composition as described herein, in an amount sufficient to increase dendritic spine density of the neuronal cell.
  • the compound of formula (I) produces a maximum number of dendritic crossings with an increase of greater than 1.0 fold by a Sholl Analysis.
  • the present disclosure provides a method for activating a serotonin receptor in a cell, either in a biological sample or in a patient, comprising administering a compound of formula (I) as defined in any one of the herein disclosed embodiments to the cell.
  • the serotonin receptor may be a 5-HT receptor subtype, preferably one or both of 5-HT2A and 5-HT2C.
  • effective amounts vary according to factors such as the disease state, age, sex and/or weight of the subject or species.
  • the amount of a given compound or compounds that will correspond to an effective amount will vary depending upon factors, such as the given drug(s) or compound(s), the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated and the like, but can nevertheless be routinely determined by one skilled in the art.
  • the compounds of formula (I) of the present disclosure are administered one, two, three or four times a year.
  • the compounds of the present disclosure are administered at least once a week.
  • the compounds are administered to the subject from about one time per two weeks, three weeks or one month.
  • the compounds are administered about one time per week to about once daily.
  • the compounds are administered 1, 2, 3, 4, 5 or 6 times daily.
  • the length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the concentration and/or the activity of the compounds of the application and/or a combination thereof.
  • the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration is required.
  • the compounds are administered to the subject in an amount and for duration sufficient to treat the subject.
  • the compounds of the application are administered at doses that are hallucinogenic or psychotomimetic and taken in conjunction with psychotherapy or therapy and may occur once, twice, three, or four times a year.
  • the compounds are administered to the subject once daily, once every two days, once every 3 days, once a week, once every two weeks, once a month, once every two months, or once every three months at doses that are not hallucinogenic or psychotomimetic.
  • a compound of formula (I) of the present disclosure may be either used alone or in combination with other known agents useful for treating diseases, disorders or conditions by activation of a serotonin receptor, such as the compounds of the present disclosure.
  • a compound of formu;a (I) is administered contemporaneously with those agents.
  • "contemporaneous administration" of two substances to a subject means providing each of the two substances so that they are both active in the individual at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art.
  • two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances. It is a further embodiment of the present application that a combination of agents is administered to a subject in a non-contemporaneous fashion.
  • a compound of formula (I) of the present disclosure is administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present application provides a single unit dosage form comprising one or more compounds of formula (I) as described herein, an additional therapeutic agent and a pharmaceutically acceptable carrier.
  • the compounds of the application are used or administered in an effective amount which comprises administration of doses or dosage regimens that are devoid of clinically meaningful psychedelic/ psychotomimetic actions. In some embodiments, the compounds of the application are used or administered in an effective amount which comprises administration of doses or dosage regimens that provide clinical effects similar to those exhibited by a human plasma psilocin Cmax of 4 ng/mL or less and/or human 5-HT2A human CNS receptor occupancy of 40% or less or those exhibited by a human plasma psilocin Cmax of 1 ng/mL or less and/or human 5- HT2A human CNS receptor occupancy of 30% or less.
  • kits in another embodiment there is provided a kit or article of manufacture including one or more compounds, pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph, and/or pharmaceutical compositions as described above.
  • kits for use in a therapeutic application mentioned above including: a container holding one or more compounds, pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph and/or pharmaceutical compositions as described herein; a label or package insert with instructions for use.
  • Example 1 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dimethylethan-1- amine (P-1): Step 1: 2-chloro-1-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (2) To a solution of 5-methoxy-1H-pyrrolo[3,2-b]pyridine (2.00 g, 13.5 mmol) in CH2Cl2 (40 mL) 0 °C under N2 was added AlCl3 (9.00 g, 67.5 mmol), followed by a solution of chloroacetyl chloride (7.62 g, 67.5 mmol) in CH2Cl2 (6 mL).
  • the mixture was stirred at 0 °C for 1.5 h, then quenched with H2O (50 mL). The pH was adjusted to 10 with saturated aqueous Na2CO3 solution. The mixture was filtered through celite, and the filter cake was washed with EtOAc (50 mL ⁇ 2). The filtrate was separated and washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated. The filter cake was stirred in EtOAc/THF (1:1, 200 mL) for 12 h.
  • Step 2 3-(2-chloroethyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine (3) To a solution of 2-chloro-1-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethan-1-one (2.00 g, 8.90 mmol) in TFA (14 mL) was added Et3SiH (7.25 g, 62.3 mmol). The reaction mixture was stirred at 25 °C for 12 h.
  • Step 4 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dimethylethan-1-amine hydrochloride (P-1 ⁇ HCl)
  • P-1 ⁇ HCl 2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylethan-1-amine hydrochloride
  • Step 1 2-(4,4-Diethoxybutyl)-1H-isoindole-1,3(2H)-dione (32)
  • 4-4-diethoxybutan-1-amine (6.80 g, 42.2 mmol)
  • ethyl 1,3-dioxo- 2,3-dihydro-1H-isoindole-2-carboxylate 9.24 g, 42.2 mmol
  • Et3N 4.27 g, 42.2 mmol
  • Step 2 2-(2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl)isoindoline-1,3-dione (33)
  • 2-(4,4-diethoxybutyl)-1H-isoindole-1,3(2H)-dione (10.0 g, 34.3 mmol)
  • 5-hydrazinyl-2-methoxypyridine (4.00 g, 28.7 mmol) in EtOH (64 mL) was added 4% v/v aqueous H 2 SO 4 (400 mL) at ambient temperature, and the mixture was then stirred at 95 °C for 4 h.
  • Step 3 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethan-1-amine (34) To a solution of 2-(2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl)isoindoline-1,3-dione (4.00 g, 12.4 mmol) in EtOH (40 mL) was added 80% hydrazine hydrate (7.79 g, 124 mmol) and the mixture was stirred at 80 °C for 12 h.
  • Step 4 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-diethylethan-1-amine (P-10) To a solution of crude 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethan-1-amine (400 mg) in MeOH (6 mL) at 0 °C was added NaBH(OAc)3 (2.22 g, 10.5 mmol), Et3N (1.06 g, 10.5 mmol) and 40% v/v aqueous acetaldehyde (575 mg, 5.22 mmol), and the mixture was then stirred at 20 °C for 12 h.
  • NaBH(OAc)3 2.22 g, 10.5 mmol
  • Et3N 1.06 g, 10.5 mmol
  • 40% v/v aqueous acetaldehyde 575 mg, 5.22 mmol
  • reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (column - Water Xbridge C18 (150*40 mm*10 ⁇ m); mobile phase: [water (NH4HCO3)-ACN]; B: 20-50%, 8 min) to provide 2- (5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dipropylethan-1-amine (20.5 mg, 5% over 2 steps) as an off-white solid.
  • Example 4 N-isopropyl-N-(2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3- yl)ethyl)propan-2-amine (P-12) To a solution of crude 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethan-1-amine (300 mg) in MeOH (5 mL) and acetone (5 mL) was added NaBH3CN (2.96 g, 47.1 mmol) and the reaction mixture was stirred at 20 °C for 12 h.
  • Scheme 3 Compounds of general formula (I) can be synthesised from the appropriately substituted 2-(1-ethanamine)aza-indole following the outlined sequence of steps in Scheme 3 or similar as one skilled in the art may consider.
  • a similar sequence of synthetic transformations as outlined in Scheme 3 proved to be a viable method of accessing compounds of general formula (I).
  • Addition of a tert-butoxy carbonyl group to the primary amine of 2-(1-ethanamine)aza-indole starting material 34 provides access to intermediate 35 which can be subjected to chemoselective reduction conditions to provide the N-methylated intermediate 36.
  • N-alkylation can be achieved with an appropriate aldehyde and reducing agent to provide compounds of general formula (I) (exemplified by P-13).
  • an appropriate aldehyde and reducing agent to provide compounds of general formula (I) (exemplified by P-13).
  • Example 4 N-ethyl-2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-N-methylethan-1- amine (P-13): Step 1: tert-butyl (2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl)carbamate (35) To a solution of 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethan-1-amine (1.40 g) in THF (10 mL) was added di-tert-butyl dicarbonate (1.68 g, 7.70 mmol) at 0 °C and the mixture was stirred at 20 °C for 2 h.
  • Step 2 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-N-methylethan-1-amine (36)
  • tert-butyl (2- (5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl)carbamate (0.60 g, 2.06 mmol) portionwise at 0 °C under nitrogen.
  • the reaction mixture was stirred at 0 °C for 6 min and then at 70 °C for 3 h under N2.
  • Step 3 N-ethyl-2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)-N-methylethan-1-amine (P-13)
  • MeOH MeOH
  • NaBH(OAc)3 2.07 g, 9.77 mmol
  • acetaldehyde 103 mg, 2.34 mmol
  • Et3N 985 mg, 9.73 mmol
  • Step 2 N-(2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl)-N-methylpropan-2-amine (P-14)
  • MeOH MeOH
  • NaBH(OAc)3 454 mg, 2.14 mmol
  • formaldehyde 32.1 mg, 1.07 mmol
  • Et3N 216 mg, 2.13 mmol
  • Example 8 2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylethan-1- amine (P-3): Step 1: 2-chloro-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (8) To a solution of 5-methoxy-1H-pyrrolo[2,3-b]pyridine (2.40 g, 16.2 mmol) in CH2Cl2 (48 mL) at 0 °C under N2 was added AlCl3 (10.8 g, 81.0 mmol), and then a solution of chloroacetyl chloride (9.15 g, 81.0 mmol) in CH2Cl2 (7 mL).
  • the reaction mixture was stirred at 0 °C for 1 h, and quenched by the addition of H2O (50 mL).
  • the pH was adjusted to 10 with saturated aqueous Na2CO3 solution.
  • the mixture was filtered through celite, and the filter cake was washed with EtOAc (50 mL ⁇ 2).
  • the filtrate was separated, and the organic layer was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 3a 2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylethan-1-amine hydrochloride (P-3 ⁇ HCl)
  • 2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N- dimethylethan-1-amine 100 mg, 0.45 mmol
  • EtOH 1 mL
  • Et2O 2 M HCl in Et2O dropwise over 10 min until the pH of the reaction solution was acidic.
  • Example 9 2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-diethylethan-1- amine (P-17): Step 1: 2-(diethylamino)-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (40) A solution of 2-chloro-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (250 mg, 1.11 mmol), NaI (250 mg, 1.67 mmol), and Et 2 NH (814 mg, 11.1 mmol) in DMAc (7 mL) was stirred at ambient temperature for 2 h at which point the reaction was diluted with water (30 mL) and then extracted with EtOAc (10 mL ⁇ 2).
  • Step 2 2-(diethylamino)-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-ol (41)
  • 2-(diethylamino)-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one 189 mg
  • MeOH MeOH
  • H2O 1.6 mL
  • NaBH4 3.00 g, 79.3 mmol
  • Step 3 2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-diethylethan-1-amine (P-17)
  • 2-(diethylamino)-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin- 3-yl)ethan-1-one (170 mg) and Et3SiH (0.20 mL, 1.25 mmol) in MeCN (4 mL) at ambient temperature was added BF3 ⁇ Et2O (0.10 mL, 0.80 mmol) and the mixture was stirred overnight.
  • Example 10 2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dipropylethan-1- amine (P-18): Step 1: 2-(dipropylamino)-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (42) A solution of 2-chloro-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (250 mg, 1.11 mmol), NaI (250 mg, 1.67 mmol) in DMAc (7 mL) was added dipropylamine (1.13 g, 11.1 mmol) and the mixture was stirred at room temperature for 2 h.w The reaction was quenched with water (30 mL) and then extracted with EtOAc (10 mL ⁇ 2).
  • Step 2 2-(dipropylamino)-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-ol (43)
  • 2-(dipropylamino)-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one 350 mg
  • MeOH MeOH
  • NaBH4 3.00 g, 79.3 mmol
  • Step 3 2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dipropylethan-1-amine (P-18)
  • 2-(dipropylamino)-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin- 3-yl)ethan-1-ol 280 mg
  • Et3SiH 0.40 mL, 2.50 mmol
  • MeCN 6 mL
  • BF3 ⁇ Et2O 0.30 mL, 2.43 mmol
  • Example 11 N-isopropyl-N-(2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3- yl)ethyl)propan-2-amine (P-19): Step 1: 2-chloro-1-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3- b]pyridin-3-yl)ethan-1-one (44) A solution of 2-chloro-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (1 g, 4.45 mmol) and DIPEA (3.00 mL, 22.0 mmol) in DMAc (10 mL) was treated with (2- (chloromethoxy)ethyl)trimethylsilane (2.50 mL, 14.1 mmol) at 0 °C and then stirred at ambient temperature for 5 h.
  • Step 2 2-(diisopropylamino)-1-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (45)
  • NaI 410 mg, 2.74 mmol
  • diisopropylamine 2.07 mL, 14.8 mmol
  • Step 3 2-(diisopropylamino)-1-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[2,3-b]pyridin-3-yl)ethan-1-ol (46)
  • 2-(diisopropylamino)-1-(5-methoxy-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one 145 mg
  • MeOH 2 mL
  • H2O 0.4 mL
  • NaBH4 3.00 g, 79.3 mmol
  • Step 4 N-isopropyl-N-(2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)propan-2- amine (P-19) To a stirred solution of crude 2-(diisopropylamino)-1-(5-methoxy-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-ol (110 mg) and Et3SiH (300 mg, 2.58 mmol) in MeCN (2 mL) at ambient temperature was added BF3 ⁇ Et2O (0.20 mL,1.62 mmol) and the mixture was stirred overnight.
  • MeCN 2-(diisopropylamino)-1-(5-methoxy-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1
  • Example 12 N-ethyl-2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylethan- 1-amine
  • Step 1 2-(ethyl(methyl)amino)-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1- one (47)
  • Step 2 2-(ethyl(methyl)amino)-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-ol (48) To a solution of crude 2-(ethyl(methyl)amino)-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin- 3-yl)ethan-1-one (205 mg) in MeOH/H2O (6/2 v/v, 8 mL) at ambient temperature was added NaBH4 (3.00 g, 79.3 mmol) and the mixture was stirred overnight.
  • Step 3 N-ethyl-2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylethan-1-amine (P-20 ⁇ HCl)
  • 2-(ethyl(methyl)amino)-1-(5-methoxy-1H-pyrrolo[2,3- b]pyridin-3-yl)ethan-1-ol 185 mg
  • Et3SiH 0.40 mL, 2.5 mmol
  • MeCN 4 mL
  • BF3 ⁇ Et2O 0.50 mL, 4.05 mmol
  • HCl salt was recovered after treatment with HCl/MeOH (1 mL) to provide N-ethyl-2-(5-methoxy- 1H-pyrrolo[2,3-b]pyridin-3-yl)-N-methylethan-1-amine hydrochloride as an off-white solid (30 mg, 12% over 3 steps).
  • Example 13 N-(2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-N- methylpropan-2-amine (P-21): Step 1: 2-(isopropyl(methyl)amino)-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan- 1-one (49) A solution of 2-chloro-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (300 mg, 1.33 mmol), NaI (300 mg, 2.00 mmol), and methyl(propan-2-yl)amine (977 mg, 13.4 mmol) in DMAc (8 mL) was stirred at ambient temperature for 2 h.
  • Step 2 2-(isopropyl(methyl)amino)-1-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan- 1-ol (50) To a solution of crude 2-(isopropyl(methyl)amino)-1-(5-methoxy-1H-pyrrolo[2,3- b]pyridin-3-yl)ethan-1-one (275 mg, 1.05 mmol) in MeOH/H2O (8 mL, v/v, 6/2) at ambient temperature was added NaBH4 (3.00 g, 79.3 mmol). The resulting mixture was stirred at ambient temperature overnight.
  • Step 3 N-(2-(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-N-methylpropan-2-amine (P-21)
  • 2-(isopropyl(methyl)amino)-1-(5-methoxy-1H-pyrrolo[2,3- b]pyridin-3-yl)ethan-1-ol 207 mg
  • Et3SiH 0.40 mL, 2.50 mmol
  • MeCN 4 mL
  • BF3 ⁇ Et2O 0.30 mL, 2.43 mmol
  • Example 14 N,N-dimethyl-2-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1- amine (P-22): Step 1: 2-chloro-1-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (52) A mixture of 5-methyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 3.78 mmol) in CH2Cl2 (15 mL) was degassed and purged with N2 three times before adding AlCl3 (2.52 g, 18.9 mmol) at 0 °C under N2.
  • Step 2 3-(2-chloroethyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine (53)
  • 2-chloro-1-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one 650 mg
  • Et3SiH 5.10 g, 43.9 mmol
  • the reaction mixture was then concentrated under reduced pressure and the residue was adjusted to pH 9 with saturated Na2CO3 solution and then extracted with EtOAc (10 mL ⁇ 3).
  • Step 3 2-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylethan-1-amine (P-22)
  • THF 3-(2-chloroethyl)-5-methyl-1H-pyrrolo[2,3-b]pyridine
  • NaI 462 mg, 3.08 mmol
  • 2 M Me2NH 2 M Me2NH in THF (1.03 mL, 2.06 mmol
  • Example 16 N,N-dimethyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1- amine (P-24): Step 1: 2-chloro-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (55) A mixture of 5-fluoro-1H-pyrrolo[2,3-b]pyridine (1.00 g, 7.35 mmol) in CH2Cl2 (7 mL) was degassed and purged with N2 three times before adding AlCl3 (4.90 g, 36.8 mmol) at 0 °C under N2.
  • Step 2 3-(2-chloroethyl)-5-fluoro-1H-pyrrolo[2,3-b]pyridine (56)
  • 2-chloro-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (1.16 g, 5.46 mmol) in TFA (10 mL)
  • Et3SiH (3.64 g, 31.3 mmol) and the reaction was stirred at ambient temperature for 12 h.
  • the reaction mixture was adjusted to pH 9 with saturated Na2CO3 solution, diluted with H2O (50 mL) and then extracted with EtOAc (75 mL ⁇ 3).
  • Example 17 N-ethyl-N-methyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1- amine (P-25): Step 1: N-ethyl-N-methyl-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-amine (P- 25) To a solution of 3-(2-chloroethyl)-5-fluoro-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.01 mmol) in DMF (5 mL) was added K2CO3 (306 mg, 2.21 mmol) and ethyl(methyl)amine (238 mg, 4.03 mmol) which was stirred at 50 °C for 12 h in a sealed tube.
  • Example 18 2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylethan-1- amine (P-4): Step 1: 2-chloro-1-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (11) To a solution of 4-methoxy-1H-pyrrolo[2,3-b]pyridine (2.20 g, 14.8 mmol) in CH2Cl2 (14 mL) was added AlCl3 (9.90 g, 74.2 mmol) and chloroacetyl chloride (8.39 g, 74.2 mmol).
  • the mixture was stirred at 0 °C for 1.5 h.
  • the reaction mixture was quenched by addition of H2O (20 mL) at 0 °C, and then adjusted to pH 9 with saturated aqueous Na2CO3 solution.
  • the mixture was filtered and extracted with EtOAc (50 mL ⁇ 2).
  • the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and set aside.
  • the filter cake was triturated with THF/EtOAc (1:1, 100 mL) at 20 °C for 2 h.
  • the filter liquor was combined with organic layers and concentrated in vacuo to give the title compound (3.10 g, 93%) as a light-yellow solid.
  • Step 3a 2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylethan-1-amine hydrochloride (P-4 ⁇ HCl)
  • 2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N- dimethylethan-1-amine 0.2 g, 0.91 mmol
  • EtOH 1 mL
  • Et2O 2 M HCl in Et2O dropwise over 10 min until the pH of the reaction solution was acidic.
  • Example 19 N,N-diethyl-2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1- amine (P-26) To a solution of 3-(2-chloroethyl)-4-methoxy-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.37 mmol) in THF (5 mL) was added NaI (534 mg, 3.56 mmol) and Et2NH (1.74 g, 23.8 mmol) and the mixture was stirred at 100 °C for 48 h. The mixture was then filtered and the filter cake was washed with THF (5 mL).
  • Example 20 N-isopropyl-N-(2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3- yl)ethyl)propan-2-amine (P-27)
  • 3-(2-chloroethyl)-4-methoxy-1H-pyrrolo[2,3-b]pyridine 500 mg, 2.37 mmol
  • NaI 534 mg, 3.56 mmol
  • diisopropyl amine (2.40 g, 23.7 mmol
  • Example 22 N-(2-(4-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-N- methylpropan-2-amine (P-29)
  • 3-(2-chloroethyl)-4-methoxy-1H-pyrrolo[2,3-b]pyridine 150 mg, 0.71 mmol
  • NaI 160 mg, 1.07 mmol
  • methyl(propan-2- yl)amine 521 mg, 7.12 mmol
  • Example 23 N,N-dimethyl-2-(4-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1- amine (P-30): Step 1: 2-chloro-1-(4-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (58) A mixture of 4-methyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 3.78 mmol) in CH2Cl2 (15 mL) was degassed and purged with N2 three times before adding AlCl3 (2.52 g, 18.9 mmol) at 0 °C under N 2 .
  • Step 2 3-(2-chloroethyl)-4-methyl-1H-pyrrolo[2,3-b]pyridine (59)
  • 2-chloro-1-(4-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one 800 mg
  • Et3SiH 4.11 g, 35.3 mmol
  • the reaction mixture was then concentrated under reduced pressure and the residue was adjusted to pH 9 with sat. aq. Na 2 CO 3 solution and then extracted with EtOAc (10 mL ⁇ 3).
  • Example 24 N-ethyl-N-methyl-2-(4-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1- amine (P-31): Step 1: N-ethyl-N-methyl-2-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-amine (P- 31) To a solution of 3-(2-chloroethyl)-4-methyl-1H-pyrrolo[2,3-b]pyridine (150 mg, 771 ⁇ mol) in DMF (3 mL) was added K2CO3 (160 mg, 1.16 mmol) and ethyl(methyl)amine (137 mg, 2.32 mmol) which was stirred at 50 °C for 12 h.
  • Example 25 N,N-dimethyl-2-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1- amine (P-32): Step 1: 2-chloro-1-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-one (61) A mixture of 4-fluoro-1H-pyrrolo[2,3-b]pyridine (700 mg, 5.14 mmol) in CH2Cl2 (15 mL) was degassed and purged with N2 three times before adding AlCl3 (3.43 g, 25.7 mmol) at 0 °C under N2.
  • Step 2 3-(2-chloroethyl)-4-fluoro-1H-pyrrolo[2,3-b]pyridine (62)
  • TFA 10 mL
  • Et3SiH 2.91 g, 25.0 mmol
  • the reaction mixture was adjusted to pH 9 with satd. aq. Na2CO3 solution, diluted with H2O (50 mL), and then extracted with EtOAc (75 mL ⁇ 3).
  • Step 3 2-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylethan-1-amine (P-32)
  • DMF dimethylethan-1-amine
  • K2CO3 306 mg, 2.21 mmol
  • 2 M dimethylamine in THF 2.01 mL
  • the reaction mixture was diluted with water (20 mL) and then extracted with EtOAc (20 mL ⁇ 5).
  • Example 26 N-ethyl-N-methyl-2-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1- amine (P-33): Step 1: N-ethyl-N-methyl-2-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethan-1-amine (P- 33) To a solution of crude 3-(2-chloroethyl)-4-fluoro-1H-pyrrolo[2,3-b]pyridine (200 mg) in DMF (5 mL) was added K2CO3 (306 mg, 2.21 mmol) and ethyl(methyl)amine (238 mg, 4.03 mmol) which was stirred at 50 °C for 12 h in a sealed tube.
  • Scheme 8 Compounds of general formula (I) can be synthesised from the appropriately substituted aza-indole following the outlined sequence of steps in Scheme 8 or similar as one skilled in the art may consider. Following a palladium catalysed methoxylation of starting reagent 13, a similar sequence of synthetic transformations as outlined in scheme 8 proved to be a viable method of accessing compounds of general formula I. Friedel-crafts acylation of aza-indole intermediate material 14 provides access to intermediate 15 which can be subjected to chemoselective silane reduction conditions to provide the alkylchloride intermediate 16. Nucleophilic displacement of the alkylchloride with a substituted amine provides compounds of general formula I (exemplified by P-5).
  • Step 1 4-methoxy-1H-pyrrolo[3,2-c]pyridine (14) To a solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (10.0 g, 65.5 mmol) in toluene (70 mL) was added t-BuONa (18.9 g, 197 mmol), Pd(OAc)2 (1.47 g, 6.55 mmol), t-Bu- Xphos (5.57 g, 13.1 mmol) and MeOH (26.5 mL). The mixture was stirred at 120 °C for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo.
  • Step 2 2-chloro-1-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-one (15) To a solution of 4-methoxy-1H-pyrrolo[3,2-c]pyridine (2.50 g, 16.9 mmol) in CH2Cl2 (15 mL) at 0 °C was added AlCl3 (11.2 g, 84.4 mmol) and chloroacetyl chloride (9.53 g, 84.4 mmol) and stirring continued at this temperature for 2 h. The reaction mixture was quenched by addition of H2O (20 mL) at 0 °C, and then adjusted to pH 9 with sat. aq. Na2CO3 solution.
  • Step 3 3-(2-chloroethyl)-4-methoxy-1H-pyrrolo[3,2-c]pyridine (16) To a solution of 2-chloro-1-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-one 15 (4.50 g, 20.0 mmol) in TFA (27 mL) was added Et3SiH (16.3 g, 140 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was adjusted to pH 9 with saturated aqueous Na2CO3 solution and extracted with EtOAc (80 mL ⁇ 2).
  • Step 1 2-(diethylamino)-1-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-one (63)
  • Step 2 2-(diethylamino)-1-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-ol (64) To a solution of crude 2-(diethylamino)-1-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3- yl)ethan-1-one (2.00 g) in MeOH (20 mL) at ambient temperature was added NaBH4 (500 mg, 13.1 mmol) and the mixture was stirred for 1 h. The reaction was quenched with water (100 mL) and extracted with CH2Cl2 (50 mL ⁇ 3).
  • Step 3 N,N-diethyl-2-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-amine (P-34)
  • P-34 To a solution of crude 2-(diethylamino)-1-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3- yl)ethan-1-ol (1.60 g) and Et 3 SiH (1.00 mL, 6.26 mmol) in MeCN (8 mL) under N 2 atmosphere at ambient temperature was added BF3 ⁇ Et2O (1.00 mL, 8.10 mmol). The resulting mixture was stirred overnight.
  • Step 5 N,N-diethyl-2-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-amine hydrochloride (P-34 ⁇ HCl) To a solution of tert-butyl 3-(2-(diethylamino)ethyl)-4-methoxy-1H-pyrrolo[3,2-c]pyridine- 1-carboxylate 65 (30 mg, 0.08 mmol) in MeOH (1 mL) was added concentrated aq. HCl (1 mL).
  • Step 2 2-(dipropylamino)-1-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-ol (67) To a solution of crude 2-(dipropylamino)-1-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3- yl)ethan-1-one (400 mg) in MeOH (5 mL) at ambient temperature was added NaBH4 (1.00 g, 26.4 mmol) and the mixture was stirred for 1 h. The reaction was quenched with water (30 mL) and extracted with CH2Cl2 (30 mL ⁇ 2).
  • Step 3 N,N-dipropyl-2-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-amine (P-35)
  • 2-(dipropylamino)-1-(4-methoxy-1H-pyrrolo[3,2-c]pyridin- 3-yl)ethan-1-ol 250 mg
  • Et3SiH 1.00 mL, 6.26 mmol
  • MeCN MeCN
  • BF3 ⁇ Et2O 1.00 mL, 8.10 mmol
  • Step 2 2-(diisopropylamino)-1-(4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[3,2-c]pyridin-3-yl)ethan-1-one (69)
  • a solution of 2-chloro-1-(4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[3,2-c]pyridin-3-yl)ethan-1-one 550 mg, 1.55 mmol
  • NaI 400 mg, 2.67 mmol
  • diisopropylamine 3.00 mL, 21.4 mmol
  • Step 3 2-(diisopropylamino)-1-(4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrrolo[3,2-c]pyridin-3-yl)ethan-1-ol (70) To a solution of crude 2-(diisopropylamino)-1-(4-methoxy-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-one (800 mg) in MeOH (10 mL) at ambient temperature was added NaBH4 (250 mg, 6.61 mmol) and the mixture was stirred for 1 h.
  • MeOH MeOH
  • NaBH4 250 mg, 6.61 mmol
  • Step 4 2-(diisopropylamino)-1-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-ol (71)
  • 2-(diisopropylamino)-1-(4-methoxy-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-ol 400 mg
  • MeCN MeCN
  • BF3.Et2O (1.50 mL, 12.2 mmol
  • the pH of the reaction solution was adjusted to 9-10 with saturated aqueous Na2CO3 solution and then extracted with CH2Cl2 (50 mL ⁇ 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate concentrated. The residue was treated with aqueous ammonium hydroxide (2 mL) in MeOH (5 mL) and stirred at ambient temperature for 16 h.
  • Step 5 N,N-diisopropyl-2-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-amine (P- 36)
  • MeCN 2-(diisopropylamino)-1-(4-methoxy-1H-pyrrolo[3,2- c]pyridin-3-yl)ethan-1-ol
  • Et3SiH 0.50 mL, 3.13 mmol
  • BF3 ⁇ Et2O 1.0 mL, 8.10 mmol
  • Step 6 tert-butyl 3-(2-(diisopropylamino)ethyl)-4-methoxy-1H-pyrrolo[3,2-c]pyridine- 1-carboxylate (72)
  • Et3N 0.20 mL, 1.43 mmol
  • DMAP 20 mg, 164 ⁇ mol
  • Boc2O 200 mg, 0.92 mmol
  • Step 7 N,N-diisopropyl-2-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-amine (P- 36 ⁇ HCl)
  • P- 36 ⁇ HCl N,N-diisopropyl-2-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-amine
  • Step 2 2-(ethyl(methyl)amino)-1-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan-1-ol (74)
  • MeOH MeOH
  • NaBH4 499 mg, 13.2 mmol
  • the reaction was quenched with water (30 mL) and extracted with EtOAc (50 mL ⁇ 2).
  • Step 3 N-ethyl-2-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)-N-methylethan-1-amine (P-37)
  • 2-(ethyl(methyl)amino)-1-(4-methoxy-1H-pyrrolo[3,2- c]pyridin-3-yl)ethan-1-ol (1.50 g) and Et3SiH (1.00 mL, 8.60 mmol) in MeCN (5 mL) at ambient temperature was added BF3 ⁇ Et2O (0.70 mL, 5.67 mmol) under N2 and the mixture was stirred overnight.
  • Step 2 2-(isopropyl(methyl)amino)-1-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethan- 1-ol (76) To a solution of crude 2-(isopropyl(methyl)amino)-1-(4-methoxy-1H-pyrrolo[3,2- c]pyridin-3-yl)ethan-1-one (350 mg) in MeOH (3 mL) at ambient temperature was added NaBH4 (100 mg, 2.64 mmol) and the mixture was stirred for 1 h. The reaction was quenched with water (100 mL) and extracted with CH2Cl2 (50 mL ⁇ 2).
  • Step 3 N-(2-(4-methoxy-1H-pyrrolo[3,2-c]pyridin-3-yl)ethyl)-N-methylpropan-2-amine hydrochloride (P-38 ⁇ HCl)
  • 2-(isopropyl(methyl)amino)-1-(4-methoxy-1H-pyrrolo[3,2- c]pyridin-3-yl)ethan-1-ol 200 mg
  • Et3SiH 0.50 mL, 3.75 mmol
  • MeCN 6 mL
  • BF 3 ⁇ Et 2 O 0.40 mL, 3.24 mmol
  • the reaction was quenched with water (50 mL) and the pH of the reaction mixture was adjusted to 9-10 with saturated aqueous NaHCO3 solution, before being extracted with CH2Cl2 (50 mL ⁇ 2).
  • the combined organic layers were washed with brine (50 mL) before being dried over Na2SO4, filtered, and the filtrate concentrated in vacuo.
  • the resulting residue was purified by preparative thin layer chromatography (CH2Cl2:MeOH:NH3(aq.), 80:10:1) to afford the title compound as the free base which was then dissolved in MeOH (1 mL) and made acidic with methanolic HCl at ambient temperature.
  • Example 36 2-(1H-indazol-3-yl)-N,N-dimethylethan-1-amine (P-56): Step 1: 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (77) To a solution of N-cyclohexyl-N-methylcyclohexanamine (17.2 g, 88.0 mmol) in THF (105 mL) was added [2-(chloromethoxy)ethyl]trimethylsilane (13.5 g, 81.0 mmol) and 4-methoxy-1H-indazole (10.0 g, 67.5 mmol).
  • Step 2 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde (78) To a solution of 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (10.0 g, 35.9 mmol) in THF (60 mL), cooled to ⁇ 65 °C, was added 2.5 M n-BuLi in hexanes (35.9 mL, 89.8 mmol) and DMF (5.25 g, 71.8 mmol). The mixture was stirred at ⁇ 65 °C for 2 h.
  • Step 3 (E)-4-methoxy-3-(2-nitrovinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (79)
  • MeNO2 6.91 mL, 129 mmol
  • NH4OAc 377 mg, 4.89 mmol
  • Step 4 (E)-4-methoxy-3-(2-nitrovinyl)-1H-indazole (80) Crude (E)-4-methoxy-3-(2-nitrovinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (6.00 g) was dissolved in 4 M HCl in MeOH (5 mL) and stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo to give (E)-4-methoxy-3-(2-nitrovinyl)-1H- indazole (3.70 g) as a yellow solid.
  • Step 5 2-(4-methoxy-1H-indazol-3-yl)ethan-1-amine (81) To an ice-cold solution of (E)-4-methoxy-3-(2-nitrovinyl)-1H-indazole (3.70 g, 16.9 mmol) in THF (37 mL) was added LiAlH4 (7.05 g, 186 mmol) portionwise. The mixture was then heated to 50 °C and stirred for 3 h. The mixture was then cooled to 0 °C and quenched by portionwise addition of Na2SO4 ⁇ 10H2O (7.00 g). The mixture was stirred at 20 °C for 10 min and then filtered.
  • Step 6 2-(4-methoxy-1H-indazol-3-yl)-N,N-dimethylethan-1-amine (P-55) To a solution of 2-(4-methoxy-1H-indazol-3-yl)ethan-1-amine (0.30 g, 1.57 mmol) in MeOH (3 mL) was added 37% w/w aqueous formaldehyde (431 mg, 5.31 mmol), AcOH (376 mg, 6.26 mmol) and NaBH3CN (197 mg, 3.13 mmol). The mixture was stirred at 20 °C for 3 h.
  • Step 7 3-(2-(dimethylamino)ethyl)-1H-indazol-4-ol (P-56)
  • CS2 CS2
  • AlCl3 297 mg, 2.23 mmol
  • Step 2 3-(2-(diethylamino)ethyl)-1H-indazol-4-ol (P-43)
  • 2-(4-methoxy-1H-indazol-3-yl)-N,N-diethylethan-1-amine 78.9 mg, 0.32 mmol
  • AlCl3 297 mg, 2.23 mmol
  • the mixture was stirred at 50 °C for 4 h at which point the reaction mixture was concentrated in vacuo then quenched with MeOH (30 mL) and concentrated again.
  • Example 38 2-(1H-indazol-3-yl)-N,N-dipropylethan-1-amine (P-45) Step 1: 2-(4-methoxy-1H-indazol-3-yl)-N,N-dipropylethan-1-amine (P-44) To a solution of 2-(4-methoxy-1H-indazol-3-yl)ethan-1-amine (200 mg, 1.05 mmol) and propanal (151 mg, 2.60 mmol) in MeOH (2 mL) at 0 °C was added AcOH (251 mg, 4.18 mmol) and NaBH3CN (164 mg, 2.61 mmol) and the mixture was stirred at 20 °C for 3 h.
  • Step 2 3-(2-(dipropylamino)ethyl)-1H-indazol-4-ol (P-45)
  • 2-(4-methoxy-1H-indazol-3-yl)-N,N-dipropylethan-1-amine 110 mg, 0.40 mmol
  • AlCl 3 799 mg, 5.99 mmol
  • the reaction mixture was concentrated in vacuo and then quenched with MeOH (30 mL) and concentrated again.
  • Example 39 3-(2-(diisopropylamino)ethyl)-1H-indazol-4-ol (P-47) Step 1: N-isopropyl-N-(2-(4-methoxy-1H-indazol-3-yl)ethyl)propan-2-amine (P-46) To a solution of 2-(4-methoxy-1H-indazol-3-yl)ethan-1-amine (300 mg, 1.57 mmol) in DCE (2 mL) was added NaBH(OAc)3 (1.20 g, 5.66 mmol) and acetone (227 mg, 3.91 mmol) and the mixture was stirred at 25 °C for 48 h.and the reaction mixture was concentrated in vacuo, then diluted with H2O (15 mL) and extracted with CH2Cl2 (30 mL ⁇ 3).
  • Step 2 3-(2-(diisopropylamino)ethyl)-1H-indazol-4-ol (P-47)
  • CS2 N-isopropyl-N-(2-(4-methoxy-1H-indazol-3-yl)ethyl)propan-2-amine
  • AlCl3 169 mg, 1.27 mmol
  • indoles Under nitrosation conditions, indoles readily convert to indazoles such as intermediate 24, subsequent Henry reaction with nitromethane provides access to nitroalkene 25. Reduction of the nitroalkene gives rise to the alkylamine 26, subsequent reductive alkylation provides compounds of general structure (I), exemplified by P-8.
  • a suitable protecting group such as a benzyl or carbamate
  • subject the protected amine to alkylation with an electrophile followed by subsequent deprotection to give rise to a secondary amine, which then can be subjected to a second alkylation with a different electrophile to give rise to compounds of general structure (I), by which the alkylamine contains alkyl groups that are dissimilar (general structure (I)).
  • Suitable protecting groups are described in Wuts, P. G. M. and Greene, T. W. ‘Greene’s Protective Groups in Organic Synthesis’ (4 th Ed.) 2006, John Wiley & Sons, Inc., Hoboken, new Jersey, USA.
  • Example 41 2-(5-methoxy-1H-indazol-3-yl)-N,N-dimethylethan-1-amine (P-8) Step 1: 5-methoxy-1H-indazole-3-carbaldehyde (24) To a solution of starting 5-methoxy-1H-indole (4.00 g, 27.1 mmol) in H2O (20 mL) and THF (7 mL) was added NaNO2 (9.38 g, 135 mmol) and 1 M aqueous HCl (135 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was extracted with EtOAc (20 mL ⁇ 3).
  • Step 2 (E)-5-methoxy-3-(2-nitrovinyl)-1H-indazole (25) To a solution of 5-methoxy-1H-indazole-3-carbaldehyde (4.50 g, 25.5 mmol) was added NH4OAc (393 mg, 5.11 mmol) and nitromethane (71 mL). The mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated in vacuo, the residue was diluted with H2O (20 mL), and then extracted with EtOAc (20 mL ⁇ 3).
  • Step 3 2-(5-methoxy-1H-indazol-3-yl)ethan-1-amine (26) To a suspension of LiAlH4 (2.08 g, 54.7 mmol) in THF (20 mL) was added (E)-5-methoxy- 3-(2-nitrovinyl)-1H-indazole (2.00 g, 9.12 mmol) in THF (10 mL) at 0 °C.
  • Step 4 2-(5-methoxy-1H-indazol-3-yl)-N,N-dimethylethan-1-amine (P-8) To an ice cold solution of crude 2-(5-methoxy-1H-indazol-3-yl)ethan-1-amine (2.00 g) in MeOH (10 mL) was added AcOH (2.51 g, 41.8 mmol) to adjust the pH to 4, followed by the addition of NaBH3CN (1.31 g, 20.9 mmol) and 37% w/w aqueous formaldehyde (2.12 g, 26.1 mmol).
  • Step 4a 2-(5-methoxy-1H-indazol-3-yl)-N,N-dimethylethan-1-amine bis-hydrochloride (P-8 ⁇ 2HCl)
  • P-8 ⁇ 2HCl 2-(5-methoxy-1H-indazol-3-yl)-N,N-dimethylethan-1-amine bis-hydrochloride
  • Step 1 5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carbaldehyde (82)
  • 5-methoxy-1H-indazole-3-carbaldehyde 15.0 g, 85.2 mmol
  • DIPEA 17.6 g, 136.2 mmol
  • 2- (chloromethoxy)ethyl)trimethylsilane 17.0 g, 102.0 mmol
  • Step 2 1-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-2- nitroethan-1-ol (83)
  • 5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3- carbaldehyde 8.60 g, 28.1 mmol
  • KO t Bu 915 mg, 8.15 mmol
  • t BuOH 50 mL
  • 1,4-dioxane 50 mL
  • Step 3 (E)-5-methoxy-3-(2-nitrovinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (84)
  • N,N-dimethylpyridin-4- amine 100 mg, 0.82 mmol
  • acetic anhydride 2.22 g, 21.7 mmol
  • Step 4 2-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)ethan-1- amine (85)
  • the reaction was quenched by sequential addition of H2O (1.76 mL), NaOH (1.76 mL, 15% aq.
  • Step 5 N,N-diethyl-2-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3- yl)ethan-1-amine (86) To a solution of 2-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3- yl)ethan-1-amine (150 mg, 0.47 mmol), DIPEA (242 mg, 1.87 mmol) and acetaldehyde (62.0 mg, 1.41 mmol) in CH2Cl2 (10 mL) was added NaBH(OAc)3 (549 mg, 2.59 mmol) in portions which was then stirred at ambient temperature for 16 h.
  • DIPEA 242 mg, 1.87 mmol
  • acetaldehyde 62.0 mg, 1.41 mmol
  • NaBH(OAc)3 549 mg, 2.59 mmol
  • Step 6 N,N-diethyl-2-(5-methoxy-1H-indazol-3-yl)ethan-1-amine (P-48) To a solution of crude N,N-diethyl-2-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-indazol-3-yl)ethan-1-amine (160 mg) in CH2Cl2 (5 mL) was added TFA (10 mL) which was then stirred at ambient temperature for 1 h.
  • Step 7 N,N-diethyl-2-(5-methoxy-1H-indazol-3-yl)ethan-1-amine bis-hydrochloride (P- 48 ⁇ 2HCl) To a solution of crude N,N-diethyl-2-(5-methoxy-1H-indazol-3-yl)ethan-1-amine (21 mg) in MeOH (0.5 mL) was added HCl (4 M in Et2O) until the reaction solution was acidic. Stirring was continued at ambient temperature for 30 min.
  • Step 2 N,N-dipropyl-2-(5-methoxy-1H-indazol-3-yl)ethan-1-amine (P-49) To a solution of crude N-(2-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol- 3-yl)ethyl)-N-propylpropan-1-amine (120 mg) in CH2Cl2 (5 mL) was added TFA (10 mL) and the reaction mixture was stirred at ambient temperature for 1 h.
  • Step 3 N,N-dipropyl-2-(5-methoxy-1H-indazol-3-yl)ethan-1-amine bis-hydrochloride (P-49 ⁇ 2HCl) Crude N,N-dipropyl-2-(5-methoxy-1H-indazol-3-yl)ethan-1-amine (24.0 mg) was dissolved in MeOH (0.5 mL) and then added to solution of 2 M HCl in Et2O (2 mL) at ambient temperature. The mixture was stirred at ambient temperature for 30 min and then concentrated under reduced pressure.
  • Example 45 N-ethyl-2-(5-methoxy-1H-indazol-3-yl)-N-methylethan-1-amine (P- 51): Step 1: tert-butyl (2-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3- yl)ethyl)carbamate (89) To a solution of 2-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3- yl)ethan-1-amine (200 mg, 0.62 mmol) and Et3N (126 mg, 1.25 mmol) in THF (20 mL) was added di-tert-butyl dicarbonate (204 mg, 0.94 mmol) and the mixture was stirred at ambient temperature for 2 h.
  • Step 2 tert-butyl ethyl(2-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3- yl)ethyl)carbamate (90) To a solution of crude tert-butyl (2-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazol-3-yl)ethyl)carbamate (197 mg) dissolved in DMF (8 mL), was added sodium hydride (23.0 mg, 0.96 mmol) at 0 °C.
  • reaction mixture was stirred at 0 °C for 30 min and then iodoethane (88.0 mg, 0.56 mmol) was added and the mixture was stirred for another 2 h.
  • the reaction mixture was quenched with saturated aq. NH4Cl (20 mL) solution and then extracted with EtOAc (20 mL ⁇ 3). The combined organic layers were washed with brine (20 mL ⁇ 2), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure.
  • the crude product was purified by flash chromatography (SiO2, petroleum ether:EtOAc, v/v, 10:1 to 4:1) to provide tert-butyl ethyl(2-(5-methoxy- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)ethyl)carbamate (160 mg) as a light yellow oil which was used in the subsequent step without further purification.
  • Step 3 N-ethyl-2-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N- methylethan-1-amine (91)
  • LiAlH4 41.0 mg, 1.08 mmol
  • Step 4 N-ethyl-2-(5-methoxy-1H-indazol-3-yl)-N-methylethan-1-amine (P-51) To a solution of crude N-ethyl-2-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- indazol-3-yl)-N-methylethan-1-amine (155 mg, 426 ⁇ mol) in THF (6 mL) at 0 °C was added 37% aqeuous HCl (3 mL) and the reaction mixture was stirred at ambient temperature overnight.
  • Example 46 N-(2-(5-methoxy-1H-indazol-3-yl)ethyl)-N-methylpropan-2-amine
  • Step 1 N-(2-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)ethyl)-N- methylpropan-2-amine (92)
  • 2-(5-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3- yl)ethan-1-amine 100 mg, 0.31 mmol
  • acetone 36.1 mg, 0.62 mmol
  • DIPEA 121 mg, 0.94 mmol
  • CH2Cl2 5 mL
  • NaBH(OAc)3 132 mg, 0.62 mmol
  • Scheme 15 Compounds of general formula (I) can be synthesised from the appropriately substituted hydroxyacetophenone following the outlined sequence of steps in Scheme 15 or similar as one skilled in the art may consider. Conversion of hydroxyacetophenone to 5-hydroxycoumarin by the use of diethylcarbonate followed by subsequent rearrangement provides the appropriate benzo[d]isoxazoles. Standard amidation processes allow for the formation of the required dialkylamide which can be converted to compounds of general structure (I) exemplified by P-9. It is not outside the scope of this application that one skilled in the art could utilise various amines that would give rise to compounds of general structure (I), by which the alkylamine contains alkyl groups that are dissimilar (general structure (I)).
  • Example 47 2-(5-methoxybenzo[d]isoxazol-3-yl)-N,N-dimethylethan-1-amine (P- 9): Step 1: 4-hydroxy-6-methoxy-2H-chromen-2-one (28) To a solution of 1-(2-hydroxy-5-methoxyphenyl)ethan-1-one (3.00 g, 18.07 mmol) in toluene (60 mL) was added sodium hydride (60% w/w in mineral oil, 2.89 g, 72.3 mmol) at 0 °C, followed by diethyl carbonate (21.6 g, 182.84 mmol). The reaction mixture was stirred at 110 °C for 16 h.
  • the reaction mixture was quenched with H2O (300 mL), the resulting layers of the biphasic mixture were separated, and the aqueous phase was washed with EtOAc (150 mL ⁇ 2). Then the aqueous phase was adjusted pH to 3 with 12 N aqueous HCl and extracted with EtOAc (200 mL ⁇ 2). The combined organic layers from the acidified extraction were dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to provide 4-hydroxy-6-methoxy-2H- chromen-2-one (3.20 g, 92%) as a white solid.
  • Step 4 2-(5-methoxybenzo[d]isoxazol-3-yl)-N,N-dimethylethan-1-amine (P-9) To a solution of 2-(5-methoxybenzo[d]isoxazol-3-yl)-N,N-dimethylacetamide ( g, 4.7 mmol) in anhydrous THF (22 mL) was added LiAlH4 (0.36 g, 9.4 mmol) at 0 °C and the reaction was stirred at ambient temperature for 3 h.
  • Step 5 2-(5-methoxybenzo[d]isoxazol-3-yl)-N,N-dimethylethan-1- amine hydrochloride (P-9 ⁇ HCl) To a solution of 2-(5-methoxybenzo[d]isoxazol-3-yl)-N,N-dimethylethan-1-amine (150 mg, 0.68 mmol) in Et2O (2 mL) was added HCl/Et2O (3 mL) until the reaction solution pH was acidic. The reaction was stirred at ambient temperature for 3 h and then concentrated in vacuo.
  • Example 48 2-(5-methoxypyrazolo[1,5-a]pyridin-3-yl)-N,N-dimethylethan-1- amine (P-54)
  • Step 1 5-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde (95)
  • POCl3 2.79 g, 18.1 mmol
  • DMF 7 mL
  • 5- methoxypyrazolo[1,5-a]pyridine 900 mg, 6.07 mmol
  • the mixture was stirred at 20 °C for 2 h, cooled to 0 °C, and diluted with H2O (10 mL).
  • Step 2 (E)-5-methoxy-3-(2-nitrovinyl)pyrazolo[1,5-a]pyridine (96) A mixture of crude 5-methoxypyrazolo[1,5-a]pyridine-3-carbaldehyde (850 mg), nitromethane (17 mL, 317 mmol) and NH4OAc (1.00 g, 13.0 mmol) was degassed and purged with N2 three times. Stirring was continued at 60 °C for 6 h under N2 and then the reaction mixture was filtered and the solid was washed with CH2Cl2 (15 mL).
  • Step 3 2-(5-methoxypyrazolo[1,5-a]pyridin-3-yl)ethan-1-amine (97) To a solution of LiAlH4 (1.61 g, 42.4 mmol) in THF (3 mL) was added (E)-5-methoxy- 3-(2-nitrovinyl)pyrazolo[1,5-a]pyridine (840 mg, 3.83 mmol) in THF (3 mL) dropwise at 0 °C. The mixture was stirred at 20 °C for 1.5 h and then quenched by addition of Na2SO4.10H2O at 0 °C.
  • Step 4 2-(5-methoxypyrazolo[1,5-a]pyridin-3-yl)-N,N-dimethylethan-1-amine (P-54) To a solution of 2-(5-methoxypyrazolo[1,5-a]pyridin-3-yl)ethan-1-amine (450 mg, 2.35 mmol) in MeOH (3 mL) and Et3N (1.64 mL, 11.8 mmol) was added 37% w/w formaldehyde (573 mg, 7.06 mmol) dropwise.
  • a 250 mM stock solution of probenecid in FLIPR calcium assay buffer (10 mL) was freshly prepared and combined with a fluorescent dye (Fluo-4 Direct) to give a final assay concentration of 2.5 mM.
  • Reference compounds were 4-fold serially diluted and the screening compounds were 3-fold serially diluted in 100% DMSO for 10 points using Agilent Bravo, and 750 nL was added to a 384 well compound plate using Echo along with 30 ⁇ L assay buffer. The fluorescent dye was then added to the assay plate along with assay buffer to a final volume of 40 ⁇ L.
  • Example 49 In vivo pharmacokinetics experiments The study was conducted using established procedures in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes, and the study protocols were reviewed and approved by the Monash Institute of Pharmaceutical Sciences Animal Ethics Committee. The systemic exposure of selected examples was studied in non-fasted male C57BL/6 mice weighing between 18.9 – 25.5 g. Mice had access to food and water ad libitum throughout the pre- and post-dose sampling period. On the day of dosing, the formulation of each compound was prepared by dissolving solid compound in phosphate buffer saline (50 mM) using vortexing, creating colourless solutions (pH 6.4-6.5) for each compound.
  • phosphate buffer saline 50 mM
  • a maximum of three blood samples were obtained from each mouse, with plasma samples being taken via submandibular bleed (approximately 120 ⁇ L).
  • plasma samples were taken via submandibular bleed (approximately 120 ⁇ L).
  • plasma samples being taken via submandibular bleed (approximately 120 ⁇ L).
  • tissue samples Pre-weighed tissue samples (brain) were homogenised using a glass rod in buffer containing an EDTA/potassium fluoride solution (0.1 M / 4 mg/mL) as a stabilisation cocktail to minimise the potential for ex vivo degradation (3 mL cocktail/g tissue).
  • Calibration standards were prepared by spiking blank brain homogenate (200 ⁇ L) with the solution standards (10 ⁇ L) and the internal standard (10 ⁇ L).
  • Table 3 Exposure parameters for a subset of exemplar compounds: P-8, P-5, P- 3, and P-1 in male C57BL/6 mice following IP administration at 10 mg/kg.
  • Example 50 Biotelemetry and Head-Twitch Response (HTR) experiments Mice (C57BL/6J males) were purchased from the Jackson Laboratory (Bar Harbor, ME, USA) at 5 ⁇ 6 weeks of age and allowed at least 1 ⁇ 2 weeks to acclimate to the NIDA, Intramural Research Program (IRP), animal research facility in Baltimore, MD, USA. The animal facility is fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care, and all procedures were approved by the NIDA IRP Animal Care and Use Committee.
  • IRP Intramural Research Program
  • mice were initially group housed 3 ⁇ 5 per cage during acclimation and housed in a 12 h light ⁇ dark cycle throughout the study, with lights on at 0700 h. Food and water were available ad libitum except during testing. Cohorts of 20 ⁇ 24 mice were used for each test drug. The mice were subjected to experimental testing once every 1 ⁇ 2 weeks for 2 ⁇ 3 months to complete dose ⁇ effect curves and antagonist experiments. A minimum of 7 days between treatments was utilized to avoid any tolerance to effects of repeated drug administration. All drug doses represent the weight of the salt dissolved in 0.9% saline vehicle. Mice were tested first in dose ⁇ response studies to assess the effects of each compound at doses from 0.03 to 30 mg/kg s.c.
  • mice received s.c. implanted temperature transponders (14 ⁇ 2 mm, model IPTT-300, Bio Medic Data Systems, Inc., Seaford, DE, USA) under brief isoflurane anesthesia. Mice were single housed post implant for the remainder of the study to protect the transponder from removal by cage mates. Temperature was determined noninvasively using a handheld receiver that is sensitive to signals emitted from the implanted transponders.
  • mice body weight and temperature were recorded prior to each experiment. Mice were then placed into testing chambers for acclimation. In dose ⁇ response studies, after a brief 5 min acclimation, mouse body temperature was recorded for baseline measurement, mice received s.c. injection of test substance or vehicle, and animals were returned to the testing arena for 30 min. During the session, locomotor activity was monitored via photobeam tracking of movements in the horizontal plane to yield distance traveled in centimeter. HTR was monitored by the analysis of GoPro Hero Black 7 video recordings (120 frames per sec and 960p resolution) using a commercially available software package from Clever Sys Inc. (Reston, VA, USA).82 Post-treatment body temperature values were also recorded, and temperature data are represented as change from pretreatment baseline.
  • mice received a s.c. injection of either receptor antagonists or vehicle and were returned to the testing chamber for 30 min. During this period, locomotor activity was monitored to examine the potential effects of antagonist treatment on general behavior or movement. At 30 min after antagonist administration, mice were given test drug or vehicle and returned to the chambers for an additional 30 min of video recording used for analyses. All statistical analyses were conducted using GraphPad Prism 9 (La Jolla, CA, USA). Dose ⁇ response data from mouse experiments were analyzed using nonlinear regression, and potency values were determined from the rising phase of the curves for HTR measures.
  • Example 51 Tail Suspension Test
  • Male ICR mice (23 ⁇ 3 g) were purchased from BioLASCO (Taipei, Taiwan) at 4-5 weeks of age and allowed 5-7 days to acclimate to the animal research facility at Pharmacology Discovery Services (Taipei, Taiwan). Mice were housed in groups of 10 in a large cage (47 x 25 x 15 cm) on a 12-hour light cycle (lights on: 0700) and provided ad libitum food and water except during acute restraint stress and tail-suspension testing. Temperature was maintained at 20-24 °C, and all rooms (colony and testing rooms) had similar lighting intensity.
  • Acute Restraint Stress (ARS) Procedure Mice were moved from the colony room to the procedure room in which ARS was to be performed.
  • ARS Acute Restraint Stress
  • mice received oral gavage of water (10 ml/kg) to avoid dehydration, and then were individually restrained for 5 hours in a clear plastic cylinder (50 mL centrifuge tube with air holes drilled for ventilation), positioned horizontally on a bench with bench towel to absorb urine. This restraint prevented physical movement, without causing pain. Restrainers were washed with veterinary disinfectant between mice. Drug Administration: Immediately after the 5-hour ARS procedure, mice were removed from the restrainers, placed in their home cage, and transported to the room in which Tail Suspension Test was to be conducted.
  • mice then received intraperitoneal injection with vehicle, ketamine (10 mg/kg), P-3 ⁇ HCl (3, 10 mg/kg) or P-8 ⁇ 2HCl (3, 10, 30 mg/kg), and were then placed back in their home cage.10 minutes after treatment, animals then underwent the Tail Suspension Test.
  • Tail Suspension Test (TST) Procedure Mice were individually suspended on the edge of a shelf, 58cm above a tabletop, using adhesive tape placed approximately 1 cm from the tip of the tail, for a total duration of 7 minutes. Using a stopwatch, the experimenters blinded to treatment groups recorded the duration of immobility (defined as hanging passively and motionless) during the 5 minutes spanning from 2-7 minutes. The data from 0-2 minutes was not recorded.
  • TST Tail Suspension Test
  • mice undergoing TST were never in view of other mice. Following TST, mice were euthanized via carbon dioxide inhalation.
  • R 1 and R 2 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C3-8 cycloalkyl and C4-14 alkylenecycloalkyl.
  • R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following: 5.
  • R 7 , R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1- 6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1-6alkyleneP(O
  • R 7 , R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1- 6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1- 6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1-6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16 alky
  • R 7 , R 8 , R 9 , R 10 and R 11 when present are each independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl and OR 13 wherein R 13 is selected from C1-6 alkyl and C1-6 haloalkyl, and the other of R 7 , R 8 R 9 , R 10 and R 11 are each hydrogen.
  • a medicament comprising a compound of any one of embodiments 1 to 31, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof.
  • a pharmaceutical composition comprising a compound of any one of embodiments 1 to 31, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof, and a pharmaceutically acceptable excipient.
  • a method of treating a disease, disorder or condition by activation of a serotonin receptor comprising administering to a subject in need thereof a compound of formula (I): or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof, wherein R 1 and R 2 are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C 2 - 6 haloalkenyl, C 2 - 6 alkynyl, C 2 - 6 haloalkynyl, C 3 - 8 cycloalkyl, C 4-14 alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C14 alkyleneheterocycloalkyl, C6-12 aryl, C7-18 alkylenearyl, C5-10 heteroaryl, and C6-16 alkyleneheteroaryl, said C1-6 alkyl, C
  • R 1 and R 2 are each independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C 3-8 cycloalkyl and C 4-14 alkylenecycloalkyl.
  • R 1 and R 2 are each independently selected from C1-4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, form any one of the following: 38.
  • R 7 , R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1- 6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 , OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, OC1-6alkyleneP
  • R 7 , R 8 R 9 , R 10 and R 11 are each independently selected from hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C1-6 alkyl, C1- 6 haloalkyl, C2-6 alkenyl, C2-C6 haloalkenyl, C2-6 alkynyl, C2-6 haloalkynyl, C1- 6 alkylamine, C1-6 alkoxy, C1-6 haloalkoxy, CO2R 13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, OC1-6alkyleneP(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C3-8 cycloalkyl, C3-14 alkylenecycloalkyl, C3-10 heterocycloalkyl, C4-16
  • a method of treating a disease, disorder or condition by activation of a serotonin receptor comprising administering to a subject in need thereof a compound of formula (I) as defined in any one of embodiments 34 to 65, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof, in combination with another known agent useful for treatment of a disease, disorder or condition by activation of a serotonin receptor.
  • a method of treating a mental illness comprising administering to a subject in need thereof a compound of formula (I) as defined in any one of embodiments 34 to 65, or a pharmaceutically acceptable salt, solvate, tautomer, N- oxide, stereoisomer, metabolite, polymorph or prodrug thereof.
  • the mental illness is selected from anxiety disorders; depression; mood disorders; psychotic disorders; impulse control and addiction disorders; drug addiction; obsessive-compulsive disorder (OCD); post- traumatic stress disorder (PTSD); stress response syndromes; dissociative disorders; depersonalization disorder; factitious disorders; sexual and gender disorders; somatic symptom disorders; hallucinations; delusions; psychosis; and combinations thereof.
  • a method for treating a central nervous system (CNS) disease, disorder or condition and/or a neurological disease, disorder or condition comprising administering to a subject in need thereof a compound of formula (I) as defined in any one of embodiments 34 to 65, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof. 70.
  • CNS central nervous system
  • the CNS disease, disorder or condition and/or neurological disease, disorder or condition is selected from neurological diseases including neurodevelopmental diseases and neurodegenerative diseases such as Alzheimer’s disease; presenile dementia; senile dementia; vascular dementia; Lewy body dementia; cognitive impairment, Parkinson’s disease and Parkinsonian related disorders such as Parkinson dementia, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infections; CNS inflammation; stroke; multiple sclerosis; Huntington’s disease; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; hereditary ataxias; neuro-otological and eye movement disorders; neurodegenerative diseases of the retina amyotrophic lateral sclerosis; tardive dyskinesias; hyperkinetic disorders; attention deficit hyperactivity disorder and attention deficit disorders; restless leg syndrome; Tourette's syndrome; schizophrenia; autism spectrum disorders; tuberous sclerosis; Rett syndrome; cerebral palsy; disorders of the reward system including eating disorders such as anorexia
  • a method for increasing neuronal plasticity and/or increasing dendritic spine density comprising contacting a neuronal cell with a compound of formula (I) as defined in any one of embodiments 34 to 65, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph or prodrug thereof, in an amount sufficient to increase neuronal plasticity and/or increase dendritic spine density of the neuronal cell.

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Abstract

La présente divulgation concerne de manière générale des composés, leurs méthodes de synthèse et leur utilisation dans le traitement de maladies mentales ou de troubles du système nerveux central.
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US12325710B2 (en) 2019-02-27 2025-06-10 The Regents Of The University Of California Substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles for treating brain disorders
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US12343337B2 (en) 2016-09-29 2025-07-01 The Regents Of The University Of California Compounds for increasing neural plasticity
US12325710B2 (en) 2019-02-27 2025-06-10 The Regents Of The University Of California Substituted 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles for treating brain disorders
US12012380B1 (en) 2021-08-12 2024-06-18 Kuleon Llc Neuroplastogens and non-hallucinogenic serotonin 5-HT2A receptor modulators
US12187678B2 (en) 2021-08-12 2025-01-07 Kuleon, LLC Methods of treating psychological disorders through the administration of serotonin 5-HT2C receptor modulators
US12275701B2 (en) 2021-08-12 2025-04-15 Kuleon, LLC Neuroplastogens and non-hallucinogenic serotonin 5-HT2A receptor modulators
US12344582B2 (en) 2021-08-12 2025-07-01 Kuleon, LLC Mixed serotonin 5-HT2A/2C receptor agonists and methods for treating pain and depression
US12441683B2 (en) 2021-08-12 2025-10-14 Kuleon, LLC 7-methyl indole analogs and dosage forms containing the same
US12295959B2 (en) 2021-12-15 2025-05-13 Delix Therapeutics, Inc. Phenoxy and benzyloxy substituted psychoplastogens and uses thereof
WO2025000053A1 (fr) * 2023-06-28 2025-01-02 Psylo Pty Ltd Composés
WO2025000051A1 (fr) * 2023-06-28 2025-01-02 Psylo Pty Ltd Composés de pyrrolopyridine pour le traitement de maladies mentales
US12415804B2 (en) 2023-06-28 2025-09-16 Psylo Pty Ltd Compounds for activating a serotonin receptor
US12428380B2 (en) 2023-06-28 2025-09-30 Psylo Pty Ltd Compounds

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